Dipeptide derivatives

ABSTRACT

A dipeptide derivative of the formula (I) is provided, which is capable of inhibiting the enzymatic activity of renin and thereby depressing the renin-angiotensin system and lowering the blood pressure, provided. ##STR1## wherein: R 1  is C 1  -C 12  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 10  cycloalkyl, aryl, or heterocyclic radical; 
     R 2  is carbamoyl, aryl, 5- or 6-membered heterocyclic radical, C 1  -C 12  alkyl-S--, C 1  -C 12  alkyl-S--CH 2  -, or C 3  -C 10  cycloalkyl-S-; 
     R 3  is aryl or 5- or 6-membered heterocyclic radical; 
     R 4  is R 4&#39;  --SO 2  or R 4&#39;  --CO; 
     R 4&#39;   is aryl, C 1  -C 12  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl; C 3  -C 10  cycloalkyl, or heterocyclic radical; 
     X is CH 2 , NH, O, or S; and 
     Y is CO or NHSO 2 , wherein R 1 , R 2 , R 3  and R 4&#39;   each may be substituted with one to three substituents.

This is a divisional application of Ser. No. 07/719,492, filed on Jun.24, 1991, now U.S. Pat. No. 5,194,608.

FIELD OF THE INVENTION

This invention relates to dipeptide derivatives capable of inhibitingthe renin activity.

PRIOR ART

The renin (EC3.4.23.15) is a protease which catalyzes the hydrolysis ofangiotensinogen into angiotensin I. The angiotensin I is a biologicallyinactive decapeptide, though it is enzymatically converted intoangiotensin II by an angiotensin converting enzyme in pulmonal vascularendotheliocytes. This system is "the renin-angiotensin system". Theangiotensin II induces hypertension through at least two routes, thatis, contractive action on smooth muscles of peripheral vasculars andstimulation of secretion of adrenal hormone which inhibits sodium ionexcretion. More particularly, it stimulates the secretion ofaldosterone, an inhibitor of the excretion of Na⁺ ion, resulting in anincrease of the volume of extracellular body fluid, which is one ofcauses hypertension. Accordingly, compounds capable of depressing orinhibiting the renin-angiotensin system are expected to be potentanti-hypertensive substance. Many peptide analogues which seemed to beuseful in the regulation of hypertensive diseases on the basis ofrenin-inhibiting activity have been developed and disclosed [forexample, U.S. Pat. No. 4,656,269, EP-A-274259 and AU-A-8822959].

As mentioned above, the renin inhibitor inhibits the synthesis ofAngiotensin I and thereby depressing the renin-angiotensin system andlowering the blood pressure. Owing to the physiological activity, renininhibitors have been used in the treatment of hypertension. However,since the hypertension is one of the most popular disorders and causesmany serious conditions and diseases, a development of more and morenovel anti-hypertensive substances including renin inhibitors has beendemanded to treat hypertension effectively.

SUMMARY OF THE INVENTION

The present inventors have now discovered a class of novel dipeptidecompounds capable of inhibiting the catalytic activity of renin both invitro and in vivo.

DETAILED DESCRIPTION

In particular, the present invention provides a dipeptide derivative offormula (I): ##STR2## wherein:

R¹ is C₁ -C₁₂ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C_(3-C) ₁₀cycloalkyl, aryl, or heterocyclic radical;

R² is carbamoyl, aryl, 5- or 6-membered heterocyclic radical, C₁ -C₁₂alkyl-S--, C₁ -C₁₂ alkyl-S--CH₂ -, or C₃ -C₁₀ cycloalkyl-S-;

R³ is aryl or 5- or 6-membered heterocyclic radical;

R⁴ is R_(4') --SO or R^(4') --CO;

R^(4') is aryl, C₁ -C₁₂ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl; C₃ -C₁₀cycloaklyl, or heterocyclic radical;

X is CH₂, NH, O or S; and

Y is CO or NHSO₂, wherein R¹, R², R³ and R^(4') each may be substitutedwith one to three substituents selected independently from a groupconsisting of hydroxy; halogen; trifluoromethyl; --CN; heterocyclicradical; C₁ -C₆ alkyl; C₃ -C₁₀ cycloalkyl; --O-C₁ -C₆ alkyl; --S-C₁ -C₆alkyl; --SO-C₁ -C₆ alkyl; --SO₂ -C₁ -C₆ alkyl; C₁ -C₆ alkylenedioxy;--CO-O-C₁ -C₆ alkyl; --NHCO-C₁ -C₆ alkyl; --NHSO₂ -C₁ -C₆ alkyl; --NR⁵R⁶ ; --O-CO-NR⁵ R⁶ ; --CO-NR⁵ R⁶ ; --O-C₁ -C₆ alkyl NR⁵ R⁶ ; R⁵ and R⁶are independently hydrogen, formyl or C₁ -C₆ alkyl, or R⁵ and R⁶, whentaken together with the nitrogen to which they are attached, form acyclic amino group, or an acid addition salt thereof.

As an another aspect of the present invention, it also provides acompound of formula (II): ##STR3## wherein, R¹ is as defined above, andR⁷ is hydrogen or an amino protecting group, which compound is useful asan intermediate for the production of the compound of formula (I).

For the purpose of the present invention, as disclosed and claimedherein, the following terms are defined as below.

The term "C₁ -C₁₂ alkyl" refers to a straight or branched saturatedhydrocarbon radical having one to twelve carbon atoms, including methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl,n-pentyl, isopentyl, 2-methylbutyl, t-pentyl, neopentyl, isopentyl,1-ethylpropyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, and the like.

The term "C₁ -C₆ alkyl" refers to a straight or branched saturatedhydrocarbon radical having one to six carbon atoms as defined above.

The term "C₂ -C₆ alkenyl" refers to a straight or branched unsaturatedhydrocarbon radical having two to six carbon atoms and one or moredouble bonds, including vinyl, allyl, 1-propenyl, isopropenyl,2-butenyl, 1,3-butadienyl, 2-pentenyl, 1-hexenyl, and the like.

The term "C₂ -C₆ alkynyl" refers to a straight or branched unsaturatedhydrocarbon radical having two to six carbon atoms and one or moretriple bonds, including ethynyl, 1-propynyl, 2-propynyl, 2-butynyl,1,3-butadiynyl, 2-pentynyl, 1-hexynyl, and the like.

The term "C₁ -C₆ alkylenedioxy" refers to methylenedioxy, ethylenedioxy,triethylenedioxy, tetramethylenedioxy, pentamethylenedioxy,hexamethylenedioxy, and the like.

The term "C₃ -C₁₀ cycloalkyl" refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, and the like.

The term "aryl" refers to aryl radicals having 6 to 10 carbon atoms,including phenyl, indenyl, naphthyl, and the like.

The term "halogen" refers to halogen atoms such as fluorine, chlorine,bromine, and iodine.

The term "cyclic amino" refers to monocyclic or bicyclic amino groupssuch as pyrrolidino, 2-pyrazolidinyl, piperidino, 1-piperazinyl,1-indolinyl, 2-indolinyl, morpholino, and the like.

The term "heterocyclic group" refers to a group of saturated orunsaturated monocyclic or condensed ring which contains one or moreheteroatoms selected from nitrogen, oxygen and sulfur. Examples ofheterocyclic groups include, for example, 2-thienyl, 3-thienyl, 2-furyl,3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 1-pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 3-pyridazinyl, 2-pyrazinyl,3-triazolyl, 2-thiazolyl, 4-thiazolyl, 5-tetrazolyl, 3-isothiazolyl,2-pyrrolidinyl, 2-imidazolidinyl, 4-pyrazolidinyl, 4-piperidyl,2-piperadinyl, 4-indolyl, 7-indolyl, 5-quinolyl, 8-quinolyl,8-isoquinolyl, morpholino and the like.

The term "5- or 6-membered heterocyclic groups" refers to 5- or6-membered heterocyclic groups as defined above.

The term "carbamoyl" refers to carbamoyl or carbamoyl substituted withone or two substituents selected from a group consisting of C₁ -C₆ alkylor C₃ -C₁₀ cycloalkyl, for example, carbamoyl, methylcarbamoyl,dimethylcarbamoyl, cyclohexylcarbamoyl, and the like.

In the definition of R¹, preferred "C₁ -C₁₂ alkyl" is methyl, ethyl,propyl, isopropyl, t-butyl, pentyl, hexyl, heptyl, or the like;preferred "C₁ -C₆ alkyl" is methyl, ethyl, propyl, isopropyl, t-butyl,or the like; preferred "C₂ -C₆ alkenyl" is vinyl, or the like; preferred"C₂ -C₆ alkynyl" is ethynyl, or the like; preferred "C₃ -C₁₀ cycloalkyl"is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like;preferred "aryl" is phenyl, naphtyl, or the like. Preferred"heterocyclic group" is 5- or 6- membered heterocyclic group such as2-thienyl, 2-furyl, 2-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-tetrazolyl,4-pyridyl, 5-pyrimidinyl, 2-pyrazinyl, 2-pyrroldinyl, 4-piperidyl, orthe like or condensed heterocyclic group such as 8-quinolyl, or thelike.

Examples of preferable R¹ include phenyl, o-tolyl, p-tolyl, m-tolyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,2,6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2,4-dibromophenyl, 2,6-dibromophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,2-tolufluoromethyl, 3-tolufluoromethyl, 4-tolufluoromethyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3,4-methylenedioxyphenyl, 3-methylaminophenyl,3-(N-formyl)methylaminophenyl, 2-dimethylaminophenyl,3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-morpholinophenyl,3-morpholinophenyl, 4-morpholinophenyl, 2-(4-methylpiperazyno)phenyl,3-(4-methylpiperazyno)phenyl, 4-(4-methylpiperazyno)phenyl,2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl,2-methylsulfonylaminophenyl, 3-methylsulfonylaminophenyl,4-methylsulfonylaminophenyl, 2-isopropoxycarbonylphenyl,3-isopropoxycarbonylphenyl, 4-isopropoxycarbonylphenyl,2-morpholinocarbonylphenyl, 3-morpholinocarbonylphenyl,4-morpholinocarbonylphenyl, 2-morpholinocarbonyloxyphenyl,3-morpholinocarbonyloxyphenyl, 4-morpholinocarbonyloxyphenyl,2-morpholinoethoxyphenyl, 3-morpholinoethoxyphenyl,4-morpholinoethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,naphtyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 5-tetrazolyl,1-methyl-5-tetrazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-4-pyridyl, 2-methyl-4-pyridyl,3-methyl-4-pyridyl, 1-chloro-4-pyridyl, 2-chloro-4-pyridyl,3-chloro-4-pyridyl, 1-fluoro-4-pyridyl, 2-fluoro-4-pyridyl,3-fluoro-4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl,1-methyl-3-pyrrolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl,1-methyl-2-piperidyl, 1-methyl-3-piperidyl, 1-methyl-4-piperidyl,8-quinolyl, methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, hexyl, heptyl, octyl, dimethylaminomethyl, morpholinomethyl,1-morpholinoisopropyl, 1-morpholinoethoxyisopropyl, 1-piperidinomethyl,cyclopropyl, cyclopentene, cyclohexyl, cycloheptyl, cyclooctyl,2-morpholinocyclohexyl, 3-morpholinocyclohexyl, 4-morpholinocyclohexyl,2-methylaminocyclohexyl, 3-methylaminocyclohexyl,4-methylaminocyclohexyl, 2-dimethylaminocyclohexyl,3-dimethylaminocyclohexyl, 4-dimethylaminocyclohexyl, and the like.

Examples of preferable R² include 5-membered heterocyclic groupcontaining two heteroatoms such as two nitrogen atoms, nitrogen andoxgen atoms, or nitrogen and sulfur atoms, for example, 4-imidazolyl,4-thiazolyl, 4-oxazolyl, or the like, wherein said heterocyclic groupmay be substituted with methyl, ethyl, isopropyl, tert-butyl, amine,methylamine, dimethylamine, diethylamine, 1-pyrrolidinyl, piperidino, orthe like; C1-C12 alkyl-S- such as methylthio, ethylthio, cyclohexylthio,or the like; C1-C12 alkyl-S-CH2-- such as methylthiomethyl, or the like;carbamoyl or substituted carbamoyl such as methylcarbamoyl,dimethylcarbamoyl, or the like.

Examples of preferable R⁴ include sulfonyl or carbonyl substituted withmethyl, ethyl, isopropyl, dimethylamino, tert-butyl, N-morpholino orN-morpholinomethyl, or the like.

Examples of more preferable R¹ are shown below. ##STR4##

Especially preferred compounds are those wherein is an optionallysubstituted 5- or 6-membered heterocyclic group; R³ is an optionallysubstituted aryl; R⁴ is morpholinosulfonyl; and X is NH.

The pharmaceutically acceptable acid addition salts of compounds offormula (I) include salts derived from a mineral acid such ashydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or the like;carboxylic acid such as oxalic acid, maleic acid, citric acid, or thelike. Preferable acid addition salts are those derived from mineralacids such as hydrochloric acid, sulfuric acid, toluenesulfonic acid,and the like.

All the compounds of the present invention are novel and can be preparedaccording to either of two processes described below on the basis ofwhat Y represents.

PROCESS I Preparation of compounds wherein Y is CO

The process is schematically shown as below. ##STR5##

In the above reaction schemes, R¹, R² and R³ are as defined above,R^(2') is optionally protected R² and R⁷ is amino-protecting group.

The amino protecting group which is shown by R⁷ can be selected fromthose groups generally used in the peptide synthesis. Examples of aminoprotecting groups include benzyloxycarbonyl (it is referred to as Z),2,6-dichlorobenzyloxycarbonyl (Z(Cl)₂), 4-nitrobenzyloxycarbonyl((Z(NO₂)), 4-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc),t-amyloxycarbonyl (Aoc), isobornyloxycarbonyl, adamantyloxycarbonyl(Adoc), 2 -(4-biphenyl)-2-propyloxycarbonyl (Bpoc),9-fluorenylmethoxycarbonyl (Fmoc), methylsulfonylethoxycarbonyl (Msc),trifluoroacetyl, phtalyl, formyl, 2-nitrophenylsulfenyl (NPS),diphenylphosphinothioyl (Ppt), dimethylphosphinothioyl (Mpt), and thelike.

Examples of the optionally protected R² shown by R² are 4-imidazoyl,4-aminothiazolyl and R² as defined above, which are optionally protectedwith a group selected from benzyl (Bzl), benzyloxycarbonyl (Z),toluenesulfonyl (tosyl or Ts), trimethylsilyl (trityl, Trt),dinitrophenyl (Dnp), 2,2,2-trifluoro-1-benzyloxycarbonylaminoethyl(Tfz), 2,2,2-trifluoro-1-t-butoxycarbonyl (TfBoc), adamantyloxycarbonyl(Adoc), piperidinocarbonyl, t-butoxycarbonyl(Boc), and the like.

Step 1

1. Preparation of Compound [3] by Aldol Reaction

a) The optically active aldehyde [1], a required starting compound, canbe prepared from, for example, Boc-L-phenylalanine using any of knownmethods described in literatures such as ¹) (T. Shioiri et al., J. Org.Chem. 52:1252 (1987) and J. Boger et al., J. Med. Chem. 28:1779 (1985)).

The aldol condensation between an aldehyde [1] and a ketone [2] iscarried out by a novel stereoselective method of the present invention.The reaction is conducted using metal amide, as a base, in an organicsolvent in the presence of a crown ether at a temperature of about -78°C. Amides which may be used include sodium bis-trimethylsilylamide(NaN(TMS)₂), potassium bis-trimethylsilylamide (KN(TMS)₂), lithiumdiisopropylamide, lithium bis-trimethylsilylamide, and the like. Crownethers which may be used include 15-crown-5, 12-crown-4, 18-crown-6, andthe like. Although all the combinations of amides and crown ethersdescribed above are suited for the stereoselective aldol reaction of theinvention, a certain combinations are especially preferable inconnection with the stereoselectivity of the product [3]which isexpressed by the ratio of the product of 2S form to 2R form, i.e.,diastereo-selectivity, 2S:2R. Thus, NaN(TMS)₂, when used in associationwith 15-crown-5, gives the most favorable result shown by the 2S:2Rvalue of about 2.4 to about 16.0, while other amides, when used alone orin combination with a crown ether, give inferior results shown by the2S:2R value of less than 2.

Solvents which may be used include ethers such as diethyl ether,tetrahydrofuran (THF), dimethoxyethane, and the like with a preferencefor THF. When toluene is used, the stereoselectivity may be relativelydecreased.

The reaction is carried out at a temperature ranging from about -20° toabout -100° C., preferably about -78° C.

b) Alternatively, the stereoselective aldol condensation reaction can becarried out using metal alkoxide as a base in an inert solvent in thepresence of a quarternary ammonium salt at a temperature of about -78°C.

Metal alkoxide which may be used include potassium t-butoxide (t-BuOK),potassium t-amyloxide (Et(Me)₂ COK) or sodium ethoxide (EtONa), and thelike.

Quarternary ammonium salts which may be used include tetrabutyl ammoniumbromide ((n-Bu)₄ NBr), tetramethyl ammonium bromide ((Me)₄ NBr),tributylbenzylammonium bromide (Bn(n-Bu)₃ NBr), and the like. All thereagents are suited to the stereoselective aldol reaction of theinvention and the best result can be obtained by the combination oft-BuOK and n-Bu₄ NBr giving the 3S/3R value of about 3.3-6.5. Thismethod is useful even in the absence of quarternary ammonium salt andgives the ratio of 3S/3R of about 3 to 5.

Solvents which may be used include THF, toluene, dichloroethane,dichloromethane, and the like with a preference for dichloromethane.When THF or toluene is used, the stereoselectivity may be decreased. Thereaction can be conducted under a similar temperature as described inabove a).

2) Separation of Stereoisomer (1S, 2S) [4]

The desired stereoisomer [3]-(2S) can be separated from a mixture ofisomers shown by formula [3] by a known resolving procedure, forexample, a column chromatography on silica gel. For the purpose of theinvention, the desired isomer can be conveniently separated by reactingthe mixture [3] with 2-methoxypropene or 2,2-dimethoxypropane in thepresence of a catalytic amounts of p-toluene sulfonic acid or pyridiniump-toluene sulfonate in a solvent such as THF or dichloroethane at atemperature ranging from room temperature to the refluxing temperaturefor about 1 to 8 hours to obtain a product containing a mixture ofring-closed compounds [4] and [5] which differ in the crystallizingproperties from a certain solvents Thus, when the product isrecrystallized from ethyl acetate or diisopropyl ether in which thedesired stereoisomer [4] is hardly soluble and the undesired isomer[5]-(2R) is soluble, the former can be separated as a crystalline solid,while the latter remains in the mother liquor. A column chromatographyon, for example, silica gel, can be used when the compound [4] is notseparated by recrystallization in ease. The so obtained compound [4] in(1S, 2S) form is a novel and useful compound as an intermediate for theproduction of the compound (I).

Alternatively, the product [3], without further treatment to formacetonide, can be directly subjected to a column chromatography onsilica gel to yield the stereoisomer [3]-(2S), which is then convertedinto dihydric alcohol of formula [7].

Step 2a

Before the deprotection of C1 amino group, the compound [4] should bereduced to avoid the possibility of ring closing reaction between thedeprotected amino group and the C₄ carbonyl group. The reducing reactioncan be carried out using any of known methods in the art. However, it isefficiently conducted by reacting a solution of the ketone [4] inethanol, methanol, THF or toluene with a reducing reagent such as sodiumborohydrate, L-selectride or Red-Al at room temperature or under coolingfor about 0.5 to 2 hours. Preferably, the latter reagent is usedslightly in excess, that is, about 1.0 to 1.3 mole to 1.0 mole of ketone[4]. The resultant product [6], a mixture of diastereoisomers (1:1 to3:1), is used in the next deprotection step without furtherpurification.

The deprotection of amino group can be carried out using any offollowing procedures. When the protecting group is Boc, and the like,the compound [6] is deprotected by dissolving into THF or dioxane,adding 6N HCl thereto, and stirring at room temperature for about 1 to 4hours. Alternatively, the compound [6] is treated with an acid such asaluminium chloride, trifluoroacetic acid or formic acid in the presenceof anisole to yield the dihydric aminoalcohol [7].

When the protecting group is a member of benzyloxycarbonyl groups suchas benzyloxycarbonyl (hereinafter, it is referred to as Z),2,6-dichlorobenzyloxycarbonyl (Z(Cl)₂), or 4-nitrobenzyloxycarbonyl((Z(NO₂)), the deprotection can be effected by catalytic reduction usingpalladium-containing catalyst, and the like. When the protecting groupis Fmoc (9-fluorenylmethoxycarbonyl), Msc(methylsulfonylethoxycarbonyl), or the like, the deprotection can beeffected by treating the compound [6] by piperidine, diethylamine, orthe like.

The resulting dihydric alcohol of formula [7] is subjected to the nextcondensation reaction without purification. The condensation can becarried out using any procedure generally used in the field of peptidesynthesis. For example, to a solution of compound [7] in an appropriatesolvent such as dichloromethane is added commercially availableN-Boc-amino acid [8] or its DCHA salt, and the mixture is allowed toreact at room temperature for about 1 to 4 hours in the presence of aslightly in excess of a coupling reagent such as 1.0 to 1.3 moleequivalent of diethyl cyanophosphosphate (DEPC) and, if desired, atertiary amine such as N-methyl morpholine to obtain a coupled compound[9] Examples of coupling reagents are DCC, EDC, DEPA, BOP, DCC-HOBt,DCC-HOSu, ethyl chlorocarbonate, isobutyl chlorocarbonate, isopropylchlorocarbonate, diethyl chlorophosphate, diphenyl chlorophosphate,2-chloro-4,6-dimethoxy-1,3,5-triazine, and the like. The compound [8]may be protected at the heterocyclic ring with a protecting groupgenerally used in the field of peptide synthesis.

The resultant diastereisomer [9] is also converted into thecorresponding ketone [10] without separation by dissolving the compound[9] into dichloromethane or DMF, adding about 3 to 10 times amounts ofactive manganese dioxide to the mixture and reacting at room temperaturefor 2 to 8 hours. This reaction proceeds very smoothly when fine crystalstarting material [9] is used. The characteristic of this reaction isthat the hydroxyl group at the C4 position of benzyl compound can beselectively oxidized.

Step 2b

Compound [10] can be also prepared through an aldol reaction accordingto a procedure described in step 1 from a starting compound [2] and adipeptide aldehyde of formula [14] obtainable from a correspondingdipeptide alcohol in the same manner as that used for the preparation ofcompound [1]. The reaction however proceeds without stereoselectivityand differs from that of step 1 in this regard. The product being a 1:1mixture of compound [10] in 2S and 2R isomers, chromatographic procedureis required for the separation of desired [10]-(2S)-isomer. Thecharacteristic of the method of step 2b is that it is applicable whenthe method of above step 2a is not effective because a compound resiststhe selective oxidization with manganese dioxide.

Step 2c

The compound [10] can be prepared by reacting a chloromethyl ketone offormula [19] with an amine. The characteristic of the method of step 2cis that it is useful in the introduction of N-substituted methylketoneresidue to the C-terminal moiety.

Step 3

The deprotection of ketone compound [10] can be carried out in the samemanner as described in the preparation of amino dihydric alcohol [7]from compound [6]. For example, when the protecting group is Boc, it iscarried out by adding excess aluminium chloride to an anisole solutionof compound [10] and stirring the mixture for about 1 to 3 hours at atemperature ranging from ice-cooled temperature to room temperature. Thedeprotection can also be effected by treating the compound [10] witheither of excess trifluoroacetic acid in anisole or 6N HCl in THF toyield the desired compound [11]. The resultant ketone [11]with carbonylgroup at the C₄ position is novel and important as an intermediate forpreparing the compound of formula (I) of the present invention.

Step 4

The compound [11] is reacted with sulfonyl propionic acid derivatives,N-sulfamyl, N-carbamoyl, or N-acyl amino acid of formula [12] which canbe prepared according to a known method such as described in aliterature (J. L. Stanton et al., J.Med.Chem. 31:1839 (1988)) under acondition for the coupling reaction and then deprotected if necessary togive the desired compound (IA) as the final product.

The coupling reaction is preferably conducted using 1.0 to 1.3 moleequivalent of diethyl cyanophosphonate (DEPC) in the presence ofN-methyl morpholine (NMM) in a solvent such as dichloromethane at roomtemperature for about 1 to 8 hours. Examples of coupling reagents areDCC, EDC, DEPA, BOP, DCC-HOBt, Ethyl chlorocarbonate, isobutylchlorocarbonate, isopropyl chlorocarbonate, diethyl chlorophosphate,diphenyl chlorophosphate, 2-chloro-4,6-dimethoxy-1,3,5-triazine, and thelike.

The deprotection of the compound [13] is carried out using any of knownprocedures depending on the protecting group. When the protecting groupof R^(2') is tosyl, it can be carried out by stirring a mixture of asolution of compound [13] in DMF in the presence of 5 to 12 moleequivalent of pyridinium hydrochloride at room temperature for about 1to 4 hours. The deprotection can be effected by means of trifluoroaceticacid (at 15° C. for about 30 minutes), HBr/acetic acid (at roomtemperature for about 30 minutes), conc.ammonia (at room temperature forabout 1 hour), conc.HCl, or the like.

PROCESS II Preparation of compounds (I) wherein Y is NHSO₂

The process is schematically shown as below. ##STR6##

In the above reaction schemes, R¹, R², R³, R⁴ and R⁷ are as definedabove.

Step 1

The optically active aldehyde [1], a required starting compound, can beprepared in the same manner as described in above Process I.

The preparation of cyanhydrin [20] from aldehyde is carried outsubstantial in accordance with a procedure described in literatures.Thus, the aldehyde [1] is allowed to react with an acidic sodium sulfiteto obtain an additive, which is then reacted with KCN in ethyl acetateat room temperature to yield the cyanhydrin [20] stereoselectively(2R/2S=3/1). The product is then resolved into each stereoisomer by acolumn chromatography on silica gel. The desired (2R)-isomer is acrystalline solid and can be purified by recrystallization while theundesired (2R)-isomer is an oil. Therefore, alternatively, the desiredproduct [20]-2R can be obtained conveniently by adding a seed crystal tothe reaction mixture, collecting the precipitate, and recrystallizingfrom a solvent before subjecting to the chromatography.

The cyanhydrin [20] is then converted into an amino alcohol [21] byreducing the nitrile group. The reduction is carried out effectively bydissolving cyanhydrin [20] into an ethereal solvent, preferably THF,adding about 2 to 2.5 mole of lithium aluminium hydride thereto. Theresulting amino alcohol [21] is then, without purification, reacted withsulfonyl chloride [22] to obtain sulfonyl amide of formula [23]. Thereaction is conducted by reacting the amino alcohol [21] and sulfonylchloride [22] in an appropriate solvent such as dichloromethane in thepresence of tertiary amine such as triethylamine at room temperature forovernight.

Step 2

The deprotection of compound [23] can be carried out in a similar manneras described in the above Process I. The deprotected compound [24] is,without purification, dissolved into an appropriate solvent such as CH₃CN, or the like, and subjected to a condensation with N-protected-aminoacid [8] in the same manner as the coupling reaction described in theabove process I to yield a dipeptide analogue [25].

Step 3

The compound [25] is then deprotected in the similar manner as that usedfor the deprotection of compound [23] in the above Process II, step 2.The product [26] is, without purification, subjected to the condensationreaction with a modified carboxylic acid [12] in the exactly same manneras described in the Process I to obtain the final product [IB].

As can be seen from the above reaction schemes, the present inventionprovides a dipeptide in which one peptide bond is formed through acoupling reaction between, for example, a free carboxyl group of anamino-protected amino acid and an amino group of an amino dihydricalcohol of formula [7] prepared from an oxazolidine derivative offormula [4]. The compound [4], an important intermediate for preparingthe compound of formula (I), is obtained by a stereoselective aldolcondensation method of the present invention. The other peptide bond isformed by a coupling reaction between a carboxylic group of, forexample, sulfonyl propionic acid of formula [12] with a free amino groupof a deprotected amino ketone [11] such as histidine as can be seen inthe step 4.

As will be hereinafter described in the Experiment, the compounds of theinvention have been demonstrated to be an effective renin inhibitor,whereby it suppresses the renin-angiotensin system (one of in vivocauses of hypertension) and lower the blood pressure. The compounds ofthe invention are low toxic and useful in the treatment of hypertensionor cardiac dysfunction through their renin inhibitory activity. Thecompounds may be administered either orally or parenterally. It ischaracteristic benefit of the compounds that they are effective evenwhen orally administered.

When the compounds of the invention are used to treat renin-associateddisorders, a therapeutically effective amount of a compound of formula(I) is formulated into a composition of an appropriate form by knownprocedures using pharmaceutically acceptable carriers, diluents, orexcipients. The administration may be conducted orally, intranasally,intravenously, subcutaneously, or the like.

For preparing the compositions for the oral administration, an activecompound (I) is mixed with one or more standard adducts such asexcipient, stabilizer, or inert diluent, and the like. The mixture isthen formulated into an appropriate form such as tablet, coated tablet,hard gelatin capsule, or an aqueous, alcoholic or oily suspension, or anaqueous, alcoholic or oily solution. Examples of inert excipients whichcan be used include various cyclodextrins, preferably β-cyclodextrin,acacia gum, magnesium carbonate, potassium phosphate, lactose, glucose,magnesium stearyl fumarate, starch, and the like. Either of dry or wetgranules can be used. Examples of oily excipients or solvents includevegetable oil such as sunflower oil and fish liver oil.

For subcutaneous or intravenous administration, an active compound or apharmaceutically acceptable salt thereof is dissolved, dispersed oremulsified into an appropriate solvent with the aid of any substancesgenerally used in such a purpose, for example, solubilizing agent,emulsifying agent, or other adjuncts to obtain solution, suspension oremulsion.

Examples of appropriate solvents include water, physiological saline,alcohols such as ethanol, propanediol or glycerol, a sugar solution suchas a solution of glucose or mannitol, or a mixture thereof, or Tween 80.Examples of solubilizing agents include above-mentioned cyclodextrins,preferably β-cyclodextrin.

The abbreviations used are as follows:

Boc=tertiary-butoxycarbonyl; Red-Al=sodiumbis(2-methoxyethoxy)aluminium, L-Selectride=lithiumtri-sec-butylborohydride; Boc His(Ts) DCHA=N.sup.α -Boc-N.sup.τ-tosyl-L-histidine dicyclohexylamine;BOP=benzotriazol-1-yl-oxy-tris-(dimethylaminophosphoniumhexafluorophosphate;DCC-HOBt=dicyclocarbodiimide-1-hydroxybenzotriazole;DCC-HOSu=dicyclohexylcarbodiimide-N-hydroxysuccineimide; DEPC=diethylcyanophosphonate; NMM=N-methylmorpholine; PPTS=pyridiniumparatoluenesulphonate; Tala=(4-thiazolyl)-L-alanine; rt=roomtemperature; Ts=tosyl; TMS=trimethylsilane;DMAP=4-dimethylaminopyridine; DCHA=Dicyclohexylamine;DCC=Dicyclohexylcarbodiimide;EDC=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; DEPA=Diethylphosphorylazide;BOP=Benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphate

The following Examples further illustrate the compounds of the inventionand the process preparing the same. The Examples are not intended to belimiting to the scope of the invention in any respect and should not soconstrued. Unless otherwise noted, the NMR spectra were measured inCDCl₃ at 200 MHz (internal standard=TMS) and IR spectra in CHCl₃. Allamino acid used is in the L-isomer.

PREPARATION 13-Boc-4-(S)-cyclohexylmethyl-2,2-dimethyl-5(S)-[2-oxo-2-(4-pyridyl)ethyl]oxazolidine [4a] ##STR7##

1. a) To a 36 ml (36 mmol, 1.5 eq) solution of 1N NaN(TMS)2 in THF isadded a solution of 4.34 g (36 mmol, 1.5 eq) of 4-acetylpyridine [2a] in20 ml of THF at -78° C. over 10 minutes under nitrogen atmosphere. After10 minutes stirring, a solution of 7.898 g (36 mmol, 1.5 eq) of15-crown-5 in 10 ml of THF is added thereto and stirred for 5 minutes.To the mixture is added 6.108 g (24 mmol) of N-Boc-L-cyclohexylalaninal[la] in 50 ml of THF over 15 minutes and stirred for 1 hour at -78° C.The reaction mixture is added to a mixture of saturated aqueous solutionof ammonium chloride and ethyl acetate with stirring and extracted threetimes with ethyl acetate. The extract is washed with saturated brine,dried over magnesium sulfate and concentrated to dryness in vacuo. Theresidue, upon purification by column chromatography on silica gel(eluent; dichloromethane/methanol=98.5:1.5) gives N-Boc-1(S)-cyclohexylmethyl-2-hydroxy-4-oxo-4-(4-pyridyl)butylamine [3a] (5.94g; yield=66.0 %) as a colorless powder. The product is a mixture ofcompound of 2(S)-isomer (desired isomer) and 2(R)-isomer (the ratio of2(S):2(R)=5.24:1).

b) To a stirring solution of 32 g (125.3 mmol) ofN-Boc-L-cyclohexylalaninal [la], 22.8 g (188 mmol, 1.5 eq) ofN-acetylpyridine, and 60.6 g (188 mmol, 1.5 eq) of tetrabutyl ammnoniumbromide in 700 ml of dichrolomethane is added each one fourth portionsof t-BuOK (21.1 g in total, 188 mmol, 1.5 eq.) at 10 minutes intervalunder cooling at -78° C. and the stirring is continued for another 1.5hours at the same temperature. The reaction mixture is added to amixture of saturated aqueous ammonium chloride and dichloromethane withstirring and extracted three times with dichloromethane. The extract istreated with citric acid to purify the basic substances to obtain acrude product [3a] (37 g; yield=79%; (S)/2(R)=7:1).

2. a) To a solution of 5.908 g (15.7 mmol) of purified alcohol [3a] in50 ml of THF are added 2 ml (20.9 mmol, 1.3 eq) of 2-methoxypropene and299 mg (1.57 mmol, 0.1 eq) of p-toluenesulfonic acid monohydrate and themixture is heated to reflux for 4 hrs. The reaction mixture isconcentrated under a reduced pressure, and the residue is alkalifiedwith 4% sodium bicarbonate and extracted 3 times with dichloromathane.The extract is washed once with saturated brine, dried over magnesiumsulfate, and concentrated to dryness. The residue is decolorized bycolumn chromatography on silica gel using a short column (eluent;dichloromethane/acetonitrile=5:1) and recrystallized from ethyl acetateto obtain 4.66 g (yield=68.6%) of the title compound [4a] as a colorlesssolid.

b) A mixture of 72 g (195.6 mmol) of the crude alcohol [3a], 150 ml(122.0 mmol, 6.2 eq) of 2,2-dimethoxypropane and 2.73 g (14.4 mmol,0.073 eq) of p-toluenesulfonic acid monohydrate in 150 ml ofdichloroethane is heated to reflux for 16 hours. After cooling, themixture is made basic with 4% aquaous sodium bicarbonate and extracted 3times with dichloromethane. The extract is washed once with saturatedbrine, dried over magnesium sulfate, concentrated to dryness in vacuo.The crude product, upon recrystallization from isopropyl ether, gives23.5 g (29.5%) of the compound [4a] as a white crystal. The motherliquor, when treated by a column chromatography on 300 g of silica gel(eluent; dichloromethane/ethyl acetate=7:1) and recrystallized in thesame manner as above, gives 2.5 g (3.1%) of compound [4a].

m.p.=115°-116° C.

[α]_(D) =-18.5° (C=1.0; CHCl₃ ; 23.5° C.)

IRνmax(CHCl₃) 1692, 1596, 1557, 1477, 1450, 1172, 1086 cm⁻¹

NMRδ (CDCl₃):1.48 (9H,s), 1.52 (3H,s), 1.60 (3H,s), 0.78-1.90 (13H,m),3.14 (1H,dd,J=16.8,6.8Hz), 3.41 (1H,dd,J=16.7,6.1Hz), 3.84 (1H,m), 4.52(1H,t like m), 7.73 (2H,m), 8.83 (2H,m)

Elemental analysis (as C₂₄ H₃₆ N₂ O₄):

Calcd.(%): C:69.20; H:8.71; N:6.73:

Found (%): C:69.20; H:8.75; N:6.76:

PREPARATION 2-20

Compounds [4], the desired stereoisomers, were prepared according to themethod described in above Preparation 1 by preparing compound [3a] andseparating the desired isomer [3]-(S) therefrom. The results are shownin the following Table 1. Among the compounds listed in the Table 1,compound Nos. 13 and 14 are separated chromatographically because thecorresponding compounds of formula [4] do not crystallize under theconditions used.

    TABLE 1      ##STR8##          [4] Compd.  [3]   [α].sub.D.sup.°     of   C-2   C =     1.0, CHCl.sub.3 Elemental   IR νcm.sup.-1 Prep. No. R.sup.1 Yield %     S/R Yield % mp °C. (°C.) analysis Calcd. Found max       2 phenyl 71 3.1 70 111˜ -17.4 C.sub.25 H.sub.37 NO.sub.4 C:     72.25 C: 72.25 1686, 1650, 1582, 1478, 1450, 1172, 1088      113 (23.5)     H: 8.98 H: 8.99         N: 3.37 N: 3.36 3 o-fluorophenyl 68 4.8 75     95˜ -18.5 C.sub.25 H.sub.36 NO.sub.4 F C: 69.25 C: 69.12 1686,     1610, 1577, 1480, 1453, 1173, 1100,      97 (24.0)  H: 8.37 H: 8.10     1086, 990, 848         N: 3.23 N: 3.23         F: 4.38 F: 4.45 4     m-methoxyphenyl 75 2.7 80 117˜ -6.2 C.sub.26 H.sub.39 NO.sub.5 C:     70.08 C: 70.05 1689, 1600, 1585, 1488, 1465, 1456, 1430,      119 (23.5)      H: 8.82 H: 8.74 1394, 1369, 1290, 1255, 1172, 1139, 1088,         N:     3.14 N: 3.15 1050 5 p-methylphenyl 78 2.4 69 132˜ -23.5 C.sub.26     H.sub.39 NO.sub.4 C: 72.69 c: 72.66 1687, 1610, 1573, 1480, 1450, 1174,     1088,      134 (24.0)  N: 3.26 N: 3.20 6 2,4- 91 4.8 69 136˜ -19.1     C.sub.25 H.sub.35 NO.sub.4 F.sub.2 C: 66.49 C: 66.31 1687, 1612(1595),     1498, 1477, 1450, 1430,  difluorophenyl    137 (23.5)  H: 7.81 H: 7.82     1172, 1140, 1098, 971, 855         N: 3.10 N: 3.04         F: 8.42 F:     8.38 7 1-naphthyl 90 1.7 60 127˜ -11.7 C.sub.29 H.sub.39 NO.sub.4     C: 74.81 C: 74.84 1687, 1595, 1508, 1477, 1449, 1393, 1379,      128     (24.0)  H: 8.44 H: 8.43 1368, 1250, 1172, 1138, 1098, 1085         N:     3.01 N: 3.06 8 3-thienyl 80 2.7 62 113˜ -13.5 C.sub.23 H.sub.35     NO.sub.4 S C: 65.52 C: 65.75 1685, 1510, 1477, 1450, 1172, 1088      114     (25)  H: 8.37 H: 8.28         N: 3.32 N: 3.31         S: 7.61 S: 7.57 9     2-thiazolyl 75 16 72 128˜ -10.7 C.sub.22 H.sub.34 N.sub.2 O.sub.4     S C: 62.53 C: 62.28 1690, 1480, 1448, 1170, 1075, 945      129 (23.5)     H: 8.11 H: 7.79         N: 6.63 N: 6.53         S: 7.59 S: 7.36       Compd.  [3] [3](S) or [4] of   C-2   [α].sub.D.sup.24 Elemental      IR ν.sub.max cm.sup.-1 Prep. No. R.sup.1 Yield % S/R Yield % mp     °C. C =      1.0, CHCl.sub.3 analysis Calcd. Found or NMR(δ)       10 m-fluorop     henyl 82 3.9 71 103˜ -15.7° C.sub.25 H.sub.36 N.sub.1     O.sub.4 F C: 69.25 C: 69.36 1690, 1610, 1590, 1485, 1475, 1443, 1392,       105   H: 8.37 H: 8.41 1170, 1086         N: 3.23 N: 3.25         F:     4.38 F: 4.22 11 p-fluorophenyl 83 2.8 61 137˜ -15.7°     C.sub.25 H.sub.36 N.sub.1 O.sub.4 F C: 69.25 C: 69.14 1685, 1600, 1505,     1475, 1450, 1392, 1170,      138   H: 8.37 H: 8.35 1155, 1085         N:     3.23 N: 3.14         F: 4.38 F: 4.41 12 2,6- 88 13.0 83 51˜     -18.8° C.sub.25 H.sub.35 N.sub.1 O.sub.4 F.sub.2 C: 66.50 C:     66.40 1691, 1624, 1588, 1467, 1450, 1394, 1369,  difluorophenyl    54     H: 7.81 H: 7.79 1279, 1174, 1139, 1089, 1030, 982, 860         N: 3.10     N: 3.34         F: 8.41 F: 8.69 13 o-methoxyphenyl 79 2.8 [3](S)     0.75˜1.93(13H, m), 1.45(9H, s),     53      3.10(1H, dd, J=9.9,     18, 3Hz), 3.70(1H, m),           4.16(1H, m), 4.82(1H, d, J=10Hz),         7.00(2H, m), 7.50(1H, td, J=2.5, 7Hz),           7.75(1H, dd, J=2.5,     7Hz) 14 o-chlorophenyl 86 3.0 [3](S)  -36.8°    0.74˜1.90(13     H, m), 1.44(9H, m),     57      3.18(2H, m), 3.71(1H, m), 4.20(1H, m),             4.75(1H, d, J=10Hz), 7.22˜7.59(4H, m) 15 m-cyanophenyl 70     2.8 68 114˜ -14.7° C.sub.26 H.sub.36 N.sub.2 O.sub.4 C:     70.88 C: 70.87 2236, 1693, 1602, 1479, 1450, 1394, 1369,      117   H:     8.24 H: 8.27 1172, 1088         N: 6.36 N: 6.16 16 o-methyl- 67 1.5 51     131˜ -3.3° C.sub.26 H.sub.40 N.sub.2 O.sub.6 S C: 61.39 C:     61.00 1691, 1656, 1607, 1578, 1496, 1453, 1394,  sulfonyl-    132   H:     7.93 H: 7.85 1369, 1342, 1279, 1156, 1089, 967, 918  aminophenyl     N: 5.51 N: 5.48         S: 6.30 S: 6.22          [4] Compd.  [3]   [α].sub.D.sup.°     of   C-2   C =     1.0, CHCl.sub.3 Elemental    Prep. No. R.sup.1 Yield % S/R Yield % mp     °C. (°C.) analysis Calcd. Found IR(ν.sub.max cm.sup.-1)       17 p-trifluoro- 75 4.9 80 128˜ -1.6 C.sub.26 H.sub.36 F.sub.3     NO.sub.4 C: 64.58 C: 64.83 1690, 1582, 1510, 1450, 1325, 1172, 1137,     methylphenyl    130 (24)  H: 7.50 H: 7.54 1066         N: 2.90 N: 2.89           F: 11.79 F: 12.02 18 m-morpholino- 70 2.7 80 154˜ -3.6     C.sub.36 H.sub.44 N.sub.2 O.sub.6 C: 68.16 C: 68.04 1690, 1632, 1484,     1451, 1438, 1394, 1369,  carbonylphenyl    157 (23)  H: 8.39 H: 8.44     1303, 1277, 1172, 1141, 1116, 1087, 1025         N: 5.30 N: 5.36 19     m-(N- 71 3.0 39 117˜ -13.5 C.sub.31 H.sub.48 N.sub.4 O.sub.6. C:     67.33 C: 67.55 1686, 1650, 1582  morpholino)-    119 (23.5) 1/4 H.sub.2     O H: 8.90 H: 8.72  ethoxyphenyl       N: 5.10 N: 5.06 20 m-(N-2-formyl)-     85 2.8 53 117˜ -16.5 C.sub.27 H.sub.40 N.sub.2 O.sub.5 C: 68.62 C:     68.68 1680, 1602, 1585, 1486, 1476, 1447, 1393  methylamino-    118     (24.0)  H: 8.53 H: 8.43 1378, 1367  phenyl       N: 5.93 N: 5.93

PREPARATION 21Boc-His(Ts)-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-(4-pyridyl)butylamide [10a] ##STR9##

To a3-Boc-4-(S)-cyclohexylmethyl-2,2-dimethyl-(S)-[2-oxo-2-(4-pyridyl)ethyl]oxazolidine[4a](4.66g, 11.18 mmol) is dissolved in ethanol (20 ml) is added sodiumborohydride (508 mg, 13.42 mmol) with stirring and ice-cooling and themixture is allowed to react at room temperature for one hour. Thesolvent is removed in vacuo. To the residue are added ice water andsaturated aqueous ammonium chloride, and the mixture is extracted withdichloromethane three times. The organic layer is washed with saturatedaqueous sodium chloride, dried over MgSO₄, and evaporated to dryness invacuo to obtain3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5(S)-[2-hydroxy-2-(4-pyridyl)ethyl]oxazolidine[6a] 4.88 g, quantitative amount) in colorless powder. The product isthen, without further purification, dissolved in THF (2 ml), and 6N HCl(16 ml) is added thereto, and the mixture is stirred at room temperaturefor one hour. The reaction mixture is neutralized with 6N NaOH,alkalified with sodium bicarbonate, and then extracted five times withdichloromethane containing 10% methanol. The extract is dried over MgSO₄and evaporated to dryness in vacuo to obtain 1(S)-cyclohexylmethyl-2(S),4-dihydroxy-4-(4-pyridyl)butylamine [7a] (3.3 g, quantitative amount,diastereomer ratio 1:1) in colorless powder. The product (3.30 g) isthen, without further purification, dissolved in dichloromethane (100ml). To the solution are added Boc-His(Ts).DCHA [8a] (8.3 g, 14.05 mmol,1.3 eq) and diethyl cyanophosphonate (2.29 g, 14.05 mmol, 1.3 eq), andthe mixture is stirred for 6 hours at room temperature. The reactionmixture is evaporated to dryness in vacuo, and the residue is purifiedwith silica gel chromatography (CH₂ Cl₂ :MeOH=95:5) to obtainBoc-His(Ts)-1(S)-cyclohexylmethyl-2(S),4-dihydroxy-4-(4-pyridyl)butylamide [9a] (6.00 g, 80%) as a mixture oftwo diastereomers. The product [9a] may be used in the followingreaction without separation of the two isomers.

To the solution of product [9a] (1.0 g, 1.45 mmol) in dichloromethane (3ml) is added MnO₂ (5 g) at room temperature, and the mixture is stirredfor six hours. The resultant black suspension is filtered on a Celitelayer overlaid with active carbon, and insoluble material on the layeris thoroughly washed with CH₂ Cl₂ -MeOH (10:1). The filtrate isevaporated to dryness in vacuo and purified with silica gelchromatography (CH₂ Cl₂ :MeOH=95:5) to obtain the title compound [10a](683 mg, 69%) in colorless powder.

NMR δ (CDCl₃): 1.34 (9H,s), 0.70-2.20(13H,m), 2.45(3H,s), 2.99(2H,m),3.03(1H,dd,J=17.8,2.3Hz), 3.34(1H,dd,J=17.8,9.6Hz),4.04(1H,ddd,J=8.7,8.7,8.7Hz), 4.23(1H,m), 4.30(1H,ddd,J=5.8,5.8,5.8Hz),6.16(1H,m), 6.47(1H,d,J=10Hz), 7.11(1H,s), 7.36(2H,d,J=8Hz), 7.80(2H,m),7.81(2H,d,J=8.6Hz), 7.92(1H,s), 8.82(2H,d,J=5Hz)

IR ν(CHCl₃)max cm⁻¹ : 3680, 3420, 3300(br), 1700, 1670, 1624, 1598,1555, 1492, 1450, 1410, 1385, 1370, 1180, 1080, 1010

PREPARATION 22 ##STR10##

A solution of N-Boc-3-cyclohexyl-alanine methyl ester [15a] (4.00 g,13.93mmol) in THF (10 ml) is stirred in the presence of 6N HCl (40 ml)at room temperature for four hours. The reaction mixture is madealkaline with powdery sodium bicarbonate and extracted withdichloromethane containing 5% methanol (100 ml×4).

The extract is dried over MgSO₄ and evaporated to dryness in vacuo toquantitatively obtain 3-cyclohexylalanine methyl ester [16a] as an oil.The product is then, without further purification, dissolved indichloromethane (50 ml). To the solution are added Boc-His(Ts).DCHA[8a](10.7 g, 18.11 mmol, 1.3 eq) and diethyl cyanophosphonate (2.95 g,18.1 mmol, 1.3 eq), and the mixture is stirred for 1.5 hours at roomtemperature. The reaction mixture is subjected to silica gelchromatography (SiO₂ :300 g, CH₂ Cl₂ :MeOH=99:1) to give a purifiedBoc-His(Ts)-3-cyclohexylalanine methyl ester [17a] (7.43 g, 93%) as anoil. To a solution of the dipeptide ester [17a](3.0 g, 5.2mmol) in THF(6 ml) and ethanol (6 ml) is added a 2N solution of lithium borohydridein THF (3 ml, 6 mmol) with stirring and ice-cooling. After 20 minutesstirring, the mixture is allowed to react at room temperature foradditional one hour. The solvent is removed in vacuo and the residueadded ice water and saturated aqueous ammonium chloride is extractedwith dichloromethane (20 ml×3). The organic layer is washed withsaturated aqueous sodium chloride, dried over MgSO₄, evaporated todryness in vacuo and the residue is purified by silica gelchromatography (SiO₂ : 200 g, CH₂ Cl₂ :MeOH=98:2) to obtainBoc-His(Ts)-3-cyclohexyl-alaninol [18a] (2.06 g, 72%) as an oil.

To a mixture of the dipeptide alcohol [18a] (2.0 g, 3.65 mmol),triethylamine (1.30 g, 12.85 mmol, 3.5 eq) and DMSO (6 ml) is added atroom temperature SO₃ pyridine (2.03 g, 12.75 mmol, 3.5 eq) in DMSO (6ml) and the mixture is stirred for 35 minutes. The reaction mixture ispoured on ice, and the resultant aqueous mixture is extracted with ethylacetate (20 ml×3) The organic layer is subsequently washed with 10%aqueous citric acid, saturated aqueous sodium chloride (×2), 7% aqueoussodium bicarbonate, and saturated aqueous sodium chloride, dried overMgSO₄, and concentrated to dryness in vacuo. The resultant residue ispurified with silica gel chromatography (SiO_(2:100) g, CH₂ Cl₂:MeOH=95:5) to obtain Boc-His(Ts)-3-cyclohexylalaninal [14a] (1.67 g,84%) in amorphous powder.

To a 0.5N potassium bis-trimethylsilylamide solution in toluene (9.2 ml,4.60 mmol, 2.5 eq) is added dropwise at -78° C. cyclohexyl methyl ketone(0.58 g, 4.60 mmol 2.5 eq) in THF (9 ml) with stirring under a nitrogenatmosphere over 10 minutes. After 20 minutes stirring at the sametemperature, 18-crown-6 (1.216 g, 4.60 mmol, 2.5 eq) in THF (10 ml) isdropwise added to the mixture over two minutes. Further, thedipeptidealdehyde [14a] (1.0 g, 1.83 mmol) in THF (10 ml) is dropwiseadded over 15 minutes at -78° C., and the mixture is stirred for onehour at the same temperature. The reaction is quenched by adding asolution of acetic acid (0.60 g, 10 mmol, 5.5 eq) in THF (10 ml) andafter the addition of saturated aqueous ammonium chloride (30 ml) themixture is extracted with ethyl acetate (50 ml×3). The organic layer iswashed with saturated aqueous sodium chloride, dried over MgSO₄,concentrated to dryness in vacuo, and purified with silica gelchromatography (Lobar column, CH₂ Cl₂ :MeOH=95:5) to obtainBoc-His(Ts)-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-cyclohexyl-butylamide[10b] (0.18 g, 15%) in amorphous powder.

NMR δ: 1.30-1.90(23H,m), 1.40(9H,s), 2.32(1H,m), 2.44(3H,s), 2.59(2H,m),2.93(1H,dd,J=5.8,9.6Hz), 3.04(1H,dd,J=5.8,9.6Hz),3.89(1H,ddd,J=8.4,8.4,8.4Hz), 3.98(1H,m), 4.30(1H,ddd,J=6.0,6.0,6.0Hz),6.12(1H,d,J=6.0Hz), 6.47(1H,d,J=9.8Hz), 7.10(1H,d,J=0.8Hz),7.36(2H,d,J=8.0Hz), 7.81(2H,d,J=8.4Hz), 7.93(1H,d,J=1.2Hz)

PREPARATION 23 ##STR11##

To a solution of cyclostatine methyl ester [27a] (700 mg, 3.05 mmol),Boc-(4-thiazolyl)-L-alanine [8c] (869 mg, 3.19 mmol, 1.05 eq), and HOBt(431 mg, 3.19 mmol, 1.05 eq) in CH₃ CN (10 ml) is added DCC (660 mg,3.20 mmol, 1.05 eq) with stirring and ice-cooling under nitrogenatmosphere and the mixture is stirred for 1.5 hours at the sametemperature and then allowed to react at room temperature for 14 hours.Ethyl acetate is added to the mixture, and precipitated crystals werefiltered off. The filtrate is concentrated to dryness in vacuo and theresidue is subjected to silica gel chromatography (SiO₂ :100 g, NH₄OH:MeOH:CH₂ Cl₂ =1:10:990) to give the aimed product,Boc-(4-thiazolyl)alanyl-cyclostatine methyl ester [28a] (830 mg, 59%) asan oil.

To the solution of the above product [28a] (830 mg, 1.72 mmol) in MeOH(2 ml) is added 1N LiOH (1.9 ml, 1.9 mmol, 1.1 eq) with stirring andice-cooling. The mixture is stirred for 10 minutes and allowed to reactat room temperature for two hours. After neutral substances are removedby washing with dichloromethane, the mixture acidified with citric acidis extracted with ethyl acetate. The organic layer is dried over MgSO₄,and concentrated to dryness in vacuo to obtain the aimed carboxylic acid[29c](700 mg, 87%).

To a mixture of the above carboxylic acid [29a](700 mg, 1.67 mmol) andN-methylmorpholine (0.17 ml, 1.67 mmol) in THF (10 ml) is added isobutylchlorocarbonate (0.2 ml, 1.67 mmol) with stirring at temperature of -15°C.--10° C. under nitrogen atmosphere, and the resultant mixture isstirred for 50 minutes at the same temperature. After precipitatedcrystals are removed by filtration, the filtrate added a solution ofdiazomethane (2.2 eq) in ethyl ether previously prepared at -10° C. isallowed to react at room temperature for 3 hours. The reaction mixtureis concentrated in vacuo to remove diazomethane and ethyl acetate (10ml) is added to the residue. After addition of 2N HCl (3 ml) at -40°C.--30° C., the mixture is allowed to react for one hour. The reactionmixture is alkalified by addition of saturated aqueous sodiumbicarbonate and the ethyl acetate layer is separated. The layer is driedover MgSO₄ and concentrated to dryness in vacuo to obtain 800 mg ofcrude chloromethyl ketone [19a]. Since the product tends to get coloredand decomposed, it is immediately used in the next step withoutpurification.

To a solution of the above product [19a] (400 mg) in MeCN (5 ml) areadded morpholine (150 mg) and catalytic amount of NaI, and the mixtureis stirred at room temperature for two hours. The reaction mixture ispurified by chromatography to give the aimed compound,Boc-(4-thiazolyl)alanyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-(N-morpholino)methyl-butylamide [10c] (Z=0) (120 mg, 29% starting from [29a])

NMRδ: 0.6-2.00(13H,m), 1.43(9H,s), 2.55(4H,m), 3.22(2H,dd,J=4.6,14.8Hz),3.26(2H,s), 3.43(1H,dd,J=5.4,14.8Hz), 3.76(4H,m), 3.89(1H,m),3.94(1H,m), 4.44(1H,ddd,J=6.2HzX3), 6.38(1H,d,J=9.8Hz),6.48(1H,d,J=7.5Hz),7.13(1H,d,J=1.8Hz), 8.79(1H,d,J=2Hz)

PREPARATION 24

In the same manner as in Preparation 23,Boc-(4-thiazolyl)alanyl-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-(N-piperidino)methyl-butylamide [10d (Z=CH₂) is obtained with a overall yield of 29%.

NMRδ: 0.6-1.83(19H,m), 1.44(9H,s), 2.46(4H,m), 3.15(2H,s),3.20(1H,dd,J=5.6,14.8Hz), 3.44(1H,dd,J=5,14.8Hz), 3.89(2H,m),4.47(1H,m), 6.41(1H,bs), 6.43(1H,d,J=9.8Hz), 7.12(1H,d,J=1.8Hz),8.78(1H,d,J=1.8Hz)

PREPARATION 25-50

Starting from the compounds [4] which have been prepared in Preparation2-20, the ketone compounds [10] are obtained in the same manner as inPreparation 21. The thus obtained products are listed in Table 2.

PREPARATION 51-57

The aldol reaction between dipeptides [14] and methyl ketones [2] givesketone compounds [10] in the same manner as in Preparation 22. The thusobtained products are listed in Table 3.

    TABLE 2      ##STR12##       Compd.   [9]  of   Yield % [10] Prep. No. R.sup.1 R.sup.2' (from [7])     Yield % IR νmax cm.sup.-1 or NMR (δ)       25 phenyl      ##STR13##      82 65 3680, 3420, 3300, 3140, 1705, 1675,1625, 1600, 1580, 1495, 1450,     1370,1162, 1125, 1032, 1010      26 o-fluorophenyl     ##STR14##      92 51 3680, 3420, 3280, 3140, 1675(1700sh), 1625, 1610, 1492, 1390,     1370,1160, 1132, 1030, 1010      27 m-methoxyphenyl     ##STR15##      100       43 0.7˜1.85(13H, m), 1.34(9H, s), 2.44(3H, s), 2.95˜3.55(2H     , m), 2.99(2H, m),3.86(3H, s), 4.02(1H, ddd, J=9.9, 9Hz), 4.20(1H, d,     J=10Hz), 4.32(1H, ddd, 6.6, 6Hz),6.09(1H, m), 6.56(1H, d, J=10Hz),     7.11(1H, d, J=1.3Hz), 7.12(1H, m), 7.35(2H, d, J`8Hz),7.48(1H, m),     7.55(1H, m), 7.37(1H, m), 7.80(2H, d, J=8.4Hz), 7.93(1H, d, J=1.4Hz)  28     p-methylphenyl      ##STR16##      78 57 3420, 3300, 3240, 1705, 1670, 1625,1608, 1495, 1450, 1370, 1122,     1033,1010      29 2,4-difluorophenyl     ##STR17##      72 50 3680, 3420, 3300(br), 1705, 1672, 1611,1599, 1496, 1450, 1430,     1384, 1370,1172, 1095, 1080, 970, 855      30 1-naphthyl     ##STR18##      71 50 3692, 3420, 1709, 1673, 1599, 1575,1495, 1450, 1386, 1370, 1175,     1094,1080, 1033, 979, 908      31 3-thienyl     ##STR19##      48 63 0.7˜85(13H, m), 1.34(9H, s), 2.44(3H, s), 2.99(2H, m),     2.86˜3.27(2H, m), 4.00(1H, ddd,J=9.9Hz), 4.19(1H, d, J=10Hz),     4.32(1H, ddd, J=6.6, 6Hz), 6.15(1H, d, J=5.0Hz), 6.54(1H, d, J=9Hz),     7.11(1H, d, J=2Hz), 7.36(2H, d, J=8.2Hz), 7.3(1H, dd, J=2.8, 5.2Hz),7.53(     1H, dd, J=1.2, 5.2Hz), 7.80(2H, d, J=8.4Hz), 7.91(1H, d, J=1.2Hz),     8.18(1H, m)      32 2-thiazolyl     ##STR20##      79  5 3420, 3300, 3140, 1703, 1670, 1625,1603, 1550(br), 1496, 1450,     1370,1165, 1123, 1032, 1010       Compd.   [9]   of   Yield %  [10] Prep. No. R.sup.1 R.sup.2' (from     [7]) Yield % IR νmax cm.sup.-1, NMR(δ), [α].sub.D.sup..deg     ree., m.p.       33 m-fluorophenyl      ##STR21##      76 45 3420, 3280, 3140, 1675, 1625, 1590,1495, 1160, 1122, 1030, 1010     34 p-fluorophenyl      ##STR22##      78 61 3420, 3320, 3140, 1670(sh 1705), 1625, 1600, 1495, 1155, 1030,     1010      35  2,6-difluorophenyl     ##STR23##      88 30 3424, 1707, 1676, 1625, 1598, 1495, 1468, 1386, 1370, 1174, 1094,     1080, 1028[α].sub.D -6.0°(C = 1.0, CHCl.sub.3, 24°     C.)      36 o-methoxyphenyl     ##STR24##      31 55 0.75˜1.83(13H, m), 1.36(9H, s), 2.44(3H, s), 3.00(2H, m),     3.13(2H, m), 3.90(3H, s),3.96(1H, ddd, J=10.10, 10Hz), 4.15(1H, m),     4.34(1H, ddd, J=7.7, 7Hz), 6.94(1H, d, J=7Hz),6.58(1H, d, J=10Hz),     6.99(2H, m), 7.10(1H, d, J=1.2Hz), 7.35(2H, d, J=8.6Hz), 7.47(1H,     m),7.70(1H, dd, J=2, 7.8Hz), 7.80(2H, d, J=8.4Hz), 7.91(1H, d, J=1.4Hz)     37 o-chlorophenyl      ##STR25##      85 27 0.74˜1.82(13H, m), 1.39(9H, s), 2.44(3H, s), 2.98(2H, m),     3.08(2H, m), 3.99(1H, m), 4.18(1H, m), 4.30(1H, ddd, J=7Hz), 6.05(1H, d,     J=7Hz), 6.52(1H, d, J=10Hz), 7.10(1H, d,J=1.3Hz), 7.27˜7.45(6H,     m), 7.60(1H, m), 7.80(2H, d, J=8.4Hz), 7.90(1H, d, J=1.4Hz)      38 m-cyanophenyl      ##STR26##      67 51 3420, 2236, 1709, 1678, 1599, 1495, 1451, 1432, 1387, 1371, 1174,     1093, 1081, 909      39 o-methyl-sulfonyl-aminophenyl     ##STR27##      76 58 3424, 1709, 1672, 1599, 1578, 1496, 1452, 1385, 1371, 1341, 1174,     1155, 1094, 1081, 1034,968, 917      40 p-trifluoro-methyl-phenyl     ##STR28##      74 37 3420, 1705, 1675, 1625, 1575, 1325,1170, 1135, 1080, 1065m.p. =     133˜135°      C.                                                   Compd.   [9]  of     Yield % [10] Prep. No. R.sup.1 R.sup.2 (from [7]) Yield % IR νmax     cm.sup.-1      NMR(δ)                                                41 m-morphol     ino-carbonylphenyl      ##STR29##      85 68 3420, 1709, 1674, 1632, 1600, 1495, 1386, 1370, 1279, 1174, 1116,     1093, 1080, 1026      42 phenyl     ##STR30##      90 57 0.70˜1.90(13H, m), 1.34(9H, s), 2.90˜3.60(4H, m),     3.99(1H, m), 4.16(1H, m),4.49(1H, ddd, J=6.2, 6.2Hz), 6.46(1H, d,     J=9.2Hz), 7.12(1H, d, J=1.8Hz),7.40˜7.63(3H, m), 7.96(2H, d,     J=8.4Hz), 8.76(1H, d, J=2Hz)      43 4-pyridyl     ##STR31##      90 64 0.70˜2.05(13H, m), 1.34(9H, s), 2.95˜3.50(4H, m),     4.01(1H, m), 4.19(1H, m),4.46(1H, ddd, J=5.8Hz), 6.4(1H, d, J=8Hz),     6.55(1H, d, J=5Hz), 7.13(1H, d, J=1.8Hz),7.78(2H, d, J=6.2Hz), 8.77(1H,     d, J=1.8Hz), 8.80(1H, d, J=9.4Hz)      44 3-thienyl     ##STR32##      86 80 0.65˜2.05(13H, m), 1.36(9H, s), 2.93(1H, d, J=17.1Hz),     3.15(1H, dd, J=17.6, 9.4Hz),3.22(1H, dd, J=14.8, 5.4Hz), 3.44(1H, dd,     J=14.6, 5.3Hz), 3.97(1H, m), 4.15(1H, m),4.48(1H, ddd, J=6.4, 6.4,     6.4Hz), 6.44(1H, d, J=9.9Hz), 6.50(1H, d, J=7.5Hz), 7.12(1H, d, J=1.9Hz),      7.30(1H, dd, J=5.1, 2.9Hz), 7.53(1H, dd, J=5.1, 1.3Hz),8.20(1H, d,     J=1.9Hz), 8.77(1H, d, J=2.1Hz)  45 m-2-(N-morpholino)-ethoxyphenyl      ##STR33##      96 51 0.70˜1.90(13H, m), 1.35(9H, s), 2.60(4H, m), 2.83(2H, t,     J=5.4Hz), 3.17(2H, m),3.22(1H, dd, J=4.6, 14.4Hz), 3.44(1H, dd, J=5.2,     14.6Hz), 3.75(4H, m), 3.98(1H, ddd,J=6.2, 2, 6.2Hz), 4.49(3H, m),     4.49(1H, ddd, J=6.2, 6.2, 6.2Hz), 6.45(2H, d, J=9.8Hz),7.11(1H, d,     J=2.0), 7.15(1H, dd, J=1.2, 2.8Hz), 7.37(1H, t, J=7.8Hz), 7.48(1H, m),     7.56(1H, dd, J=7.8Hz), 8.77(1H, d, J=2.0Hz)  46 m-(N-formyl)-methylamino      ##STR34##      97 77 0.70˜1.86(13H, m), 1.33(9H, s), 3.00(1H, dd, J=0.5,     14.8Hz), 3.23(1H, dd, J=5.2, 14.8Hz),3.36(3H, s), 3.40(3H, m), 4.01(1H,     m), 4.20(1H, d, J=9.8Hz), 4.47(1H, ddd, J=5Hz),6.44(1H, d, J=9.8Hz),     6.58(1H, d, J=6.4Hz), 7.14(1H, d, J=1.8Hz), 7.39(1H, ddofd,J=1.2, 2.4,     8Hz), 7.52(1H, t, J=7.8Hz), 7.87(2H, m), 8.57(1H, s), 8.78(1H, d, J=2Hz)      47 4-pyridyl     ##STR35##      87 61 0.77˜1.84(13H, m), 2.70(3H, s), 3.17(4H, m), 4.03(1H, m),     4.20(1H, m), 4.42(1H, ddd,J=5.8Hz×3), 6.42(1H, d, J=5Hz), 6.49(1H,     d, J=10Hz), 6.89(1H, s), 7.80(2H, m), 7.80(2H, m), 8.81(2H, m)       Compd.   [9]  of   Yield % [10] Prep. No. R.sup.1 R.sup.2 (from [7])     Yield % IR νmax cm.sup.-1 or NMR(δ)       48 phenyl      ##STR36##      62 89 0.77˜1.82(13H, m), 1.38(9H, s), 3.10(4H, m), 4.03(1H, m),     4.16(1H, m), 4.41(1H, t,J=5.2Hz), 6.71(1H, s), 6.89(1H, d, J=8.2Hz),     7.47(2H, t, J=7.8Hz), 7.59(1H, m),7.94(2H, d, J=7.2Hz), 8.47(1H, s)  49     4-pyridyl CONH.sub.2 86 65 0.76˜1.82(13H, m), 1.41(9H, s),     2.67(2H, m), 3.06(1H, dd, J=4.2, 18Hz), 3.27(1H, dd,      J=8.4, 18Hz),     4.04(1H, m), 4.24(1H, m), 4.37(1H, t, J=6.4Hz), 7.07(1H, d, J=9.4Hz),       7.85(2H, m), 8.76(2H, m) 50 4-pyridyl SMe 66 36 0.82˜1.88(13H,     m), 1.38(9H, s), 2.15(3H, s), 2.87(1H, dd, J=6.4, 13.6Hz), 2.95(1H, t,        J=7.6Hz), 3.10(1H, dd, J=2.2, 18.8Hz), 3.42(1H, dd, J=9.4, 18.6Hz),     4.12(1H, m),      4.23(1H, ddd, J=6Hz×3), 4.28(1H, m), 5.37(1H, d,     J=6Hz), 6.55(1H, d, J=10Hz), 7.77(2H, m),      8.82(2H, m)

    TABLE 3      ##STR37##       Compd.     of Prep. No. R.sup.1 R.sup.2' Yield % NMR δ      (CDCl.sub.3)            51 p-methoxy-phenyl      ##STR38##      10 0.75˜1.94(13H, m), 1.33(9H, s), 2.44(3H, s), 3.00(2H, m),     3.08(2H, m), 3.88(3H, s), 4.01(1H, ddd, J= 8.2Hz), 4.19(1H, m), 4.34(1H,     ddd, J=6.4Hz), 6.12(1H, d, J=5.8Hz), 6.58(1H, d, J=9.8Hz), 6.93(2H,     d,J=8.6Hz), 7.11(1H, s), 7.36(2H, d, J=8.2Hz), 7.81(2H, d, J=8.6Hz),     7.93(1H, s), 7.95(2H, d, J=9Hz)  52 3',4'-methyl-lenedioxyphenyl      ##STR39##      19 0.77˜1.83(13H, m), 1.34(9H, s), 2.44(3H, s), 3.00(4H, m),     4.00(1H, ddd, J=8.4, 8.4, 8.4Hz),4.18(1H, d, J=6.2Hz), 4.32(1H, ddd,     J=6Hz), 6.05(2H, s), 6.13(1H, m), 6.54(1H, d, J=9.8Hz),6.85(1H, d,     J=8.2Hz), 7.11(1H, d, J=0.4Hz), 7.36(2H, d, J=8.4Hz), 7.43(1H, d,     J=1.4Hz),7.58(1H, td, J=8.2, 0.8Hz), 7.80(2H, d, J=8.4Hz), 7.92(1H, d,     J=1.2Hz)      53 3-thienyl     ##STR40##      23 Identical with those of compound in Ex. No. 27      54 morpholino-carbonyloxy-phenyl      ##STR41##      27 0.72˜2.00(13H, m), 1.34(9H, s), 2.44(3H, s), 3.00(2H, m),     3.10(2H, m), 3.52˜3.8(8H, m),4.00(1H, ddd, J=8Hz), 4.18(1H, m),     4.33(1H, ddd, J=6.6Hz), 6.10(1H, m), 6.58(1H, d, J=7Hz),7.12(1H, d,     J=3.4Hz), 7.36(3H, m), 7.47(1H, t, J=8Hz), 7.68(1H, m), 7.82(3H, m),     7.94(1H, d, J=1.4Hz)      55 phenyl     ##STR42##      28 Identical with those of compound in Ex. No. 21      56 N-methyl-3-pyrrolyl      ##STR43##      39 0.70˜1.85(13H, m), 1.38(9H, S), 2.81(2H, d, J=5.6Hz), 3.20(1H,     dd, J=4.8, 14.2Hz)3.45(1H, dd, J=5.2, 14.8Hz), 3.69(3H, S), 3.92(1H, m),     4.07(1H, t, J=5.8Hz), 4.49(1H, ddd, J=6.8Hz×3) 6.48(1H, d,     J=9.6Hz), 6.57(1H, S), 6.58(1H, S), 7.12(1H, d, J=2Hz), 7.32(1H, S),     8.77(1H, d, J=2Hz)      57 cyclohexyl     ##STR44##      31 0.6˜1.92(13H, m), 2.33(1H, m), 2.45˜2.75(2H, m),     3.20(1H, dd, J=14.4, 5.2Hz)3.44(1H, dd, J= 14.8, 3.8Hz), 3.85(1H, m),     3.93(1H, m), 4.45(1H, ddd, J=6.2, 6.2, 6.2Hz)6.40(1H, d, J=9.8Hz),     6.49(1H, d, J=6.8Hz), 7.12(1H, d, J=1.6Hz), 8.78(1H, d, J=1.8Hz)

PREPARATION 58 ##STR45##

To a suspension of methyl ester of L-phenylalanine hydrochloride [31a](4.31 g, 20 mmol) in dichloromethane (50 ml) are addedN-methylmorpholine (6.7 g, 66 mmol, 3.3 eq). N-Morpholinosulfonylchloride [30a] (4.44 g, 24 mmol, 1.2 eq) in dichloromethane (4 ml) andsubsequently DMAP (244 mg, 2.0 mmol, 0.1 eq) and the mixture is stirredovernight at room temperature. The reaction mixture is washed with INHCl and H20 and the dichloromethane layer is dried over MgSO₄ andconcentrated to dryness in vacuo. The residue is subjected to silica gelcolumn chromatography (SiO₂ 110 g, CH₂ Cl₂ :MeOH=20:1) to obtain thecompound [32a] (5.16 g, 79%).

(i) To a solution of the compound [32a] (2.666 g, 8.1 mmol) in MeOH (12ml) is added 1N LiOH (12 ml, 12 mmol, 1.5 eq) and the mixture is stirredat 80° C. for 30 minutes. After removal of MeOH in vacuo, the reactionmixture is washed with ethyl acetate. The mixture is then treated withactive carbon, adjusted to pH 2-3 with 1N HCl, and extracted with ethylacetate. The extract is washed with saturated aqueous sodium chloride,dried over MgSO₄, and concentrated to dryness in vacuo. The residue isrecrystallized from ethyl acetate/n-hexane to obtain colorless needle ofN-(N-morpholino)sulfonyl-phenylalanine [12b] (2.267 g, 89%). m.p.164°-6° C. (decomposition)

(ii) To the compound [32b] (E=Et) (920 mg, 2.7 mmol) are added 6N HCl(9.2 ml) and acetic acid (2 ml) and the mixture is heated with stirringon an oil bath of 100° C. for one hour. After cooling, the reactionmixture is concentrated to dryness in vacuo. The residue is madealkaline by dissolving into saturated aqueous sodium bicarbonate. Theaqueous solution is washed with dichloromethane (10 ml×3), treated withactive carbon, and neutralized with 6N HCl. The solution is then madeacidic up to pH 3 by addition of 10% aqueous citric acid and extractedwith ethyl acetate (50 ml×3). The organic layer is washed with saturatedaqueous sodium chloride (×2), dried over MgSO₄, and concentrated todryness in vacuo to give the compound [12c]as a crystalline residue (620mg, 74%). Recrystallization from dichloromethane/isopropyl ether affordswhite crystals (543 mg, 64%). m.p. 157°- 158° C.

[α]_(D) =-17.7±0.6° (C=1.0; MeOH; 25.0° C.)

IRνmax(cm⁻¹): 3320, 3200-2600(br), 1750, 1603, 1585, 1500, 1455, 1400,1352, 1300

NMR(δ): 2.93(5H,m), 3.17(1H,dd,J=5.2,14.2Hz), 3.54(4H,m),4.11(1H,dd,J=5.2,8.6Hz), 7.30(5H,m)

PREPARATION 59 ##STR46##

a) A solution of methyl ester of N-Boc-ω-benzyl-L-aspartic acid [33a](52.7 g, 0.156 mmol) in a mixture of water (10 ml), acetic acid (10 ml)and methanol (150 ml) is subjected to a catalytic reduction in thepresence of 10% Pd-C (4.0 g) under a atmosphere of hydrogen gas at roomtemperature. The reduction is conducted with stirring and underatmospheric pressure. After 3-hour reaction, the catalyst is filtered ofand the filtrate is evaporated to dryness in vacuo. The residue isdissolved in saturated aqueous sodium bicarbonate and the aqueous layeris washed with dichloromethane (50 ml×3), made acidic with citric acid(about pH3), and extracted with ethyl acetate (200 ml×4) while saltingout with the addition of sodium chloride. The ethyl acetate layer isdried over MgSO₄ and concentrated to dryness in vacuo. Trituration ofthe residue with the addition of n-hexane affords the carboxylic acid[34a] (37.5 g, 98%) as a white solid.

To a solution of the above product [34a] (18.8 g, 76 mmol) andN-methylmorpholine (7.8 g, 77.1 mmol, 1.0 eq) in ethyl ether (200 ml) isadded isobutyl chlorocarbonate (9.92 ml, 76.5 mmol, 1.0 eq) over 10minutes at temperature between -15° C. and -10° C. under nitrogenatmosphere, and the mixture is stirred at the same temperature for 30minutes. Precipitated methylmorpholine hydrochloride is filtered off,and the filtrate is added to a solution of diazomethane in ethyl etherwhich has previously been prepared from nitrosomethylurea (37 g, 359mmol) with stirring at -10° C. over 5 minutes. After 2.5-hour stirringat room temperature, the mixture is concentrated in vacuo to removeexcessive diazomethane. To the mixture is added ethyl acetate (150 ml)and then dropwise added 2N HCl/ethyl acetate (45 ml) at temperaturebetween -40° C. and -30° C. After 30-minute stirring, the mixture isneutralized with saturated aqueous sodium bicarbonate. The ethyl acetatelayer is separated, dried over MgSO₄, evaporated to dryness in vacuo,and subjected to silica gel chromatography (SiO₂ : 150 g, AcOEt:C₂ Cl₂=6:1) to obtain the chloromethyl ketone [36a](20.3 g, 95%) as an oil.

To a solution of the above compound [36a] (40.3 g, 144.1 mmol) in MeCN(160 ml) are added CaCO₃ (28 g, 280 mmol, 1.9 eq) and thioformamide(HCSNH₂, 14 g, 229.1 mmol, 1.6 eq) and the mixture is stirred at roomtemperature for 18 hours under nitrogen atmosphere. Insoluble materialsare filtered off and the filtrate is concentrated to dryness in vacuoThe residue is dissolved in dichloromethane, subsequently washed with 7%aqueous sodium bicarbonate, 1N NaOH, and water, two times each, toremove non-reacted thioformamide. The dichloromethane layer is driedover MgSO₄, concentrated to dryness in vacuo, and subjected to silicagel chromatography (SiO₂ : 370 g, MeCN CH₂ Cl₂ =1:7) to obtain(4-thiazolyl)alanine derivative [37a] (29.15 g, 71%) as an oil.

To the solution of above product [37a] (29.1 g, 101.6 mmol) inmethanol(120 ml) is added 1N LiOH (112 ml, 112 mmol, 1.1 eq) withstirring and ice-cooling and the mixture is stirred for ten minutes atthe same temperature and allowed to react for additional one hour atroom temperature. The reaction mixture is concentrated in vacuo on awater bath below 30° C. to remove methanol and the residue is washedthree times with dichloromethane. The aqueous layer is treated withactive carbon, added with citric acid to adjust the pH to 3, andextracted with ethyl acetate (150 ml×3). To the organic layer washed twotimes with saturated aqueous sodium chloride are added MgSO₄ and activecarbon, the mixture is filtered and the filtrate is concentrated todryness in vacuo to obtain crystalline crude product [8b] (26.96 g,97%). Recrystallization of the product from n-hexane provides pureproduct [8b] (26.2 g, 95%). m.p. 96°-98° C.

[α]_(D) =-4.2° (c=2; MeOH; 24° C.)

NMR(δ): 1.47(9H,s), 3.41(1H,dd,J=5.6,14.6Hz), 3.56(1H,dd,J=3.4,11.0Hz),4.59(1H,m), 3.60(1H,d,J=3.6Hz), 7.14(1H,d,J=2Hz), 8.94(1H,d,J=2Hz)##STR47##

i) Preparation of carbonic anhydride

To a solution of compound [34a] (500 mg, 2.02 mmol) andN-methylmorpholine (225 mg, 2.22 mmol, 1.1 eq) in toluene (4 ml) isadded isopropyl chlorocarbonate (0.254 ml, 2.22 mmol, 1.1 eq) withstirring at temperature between -15° C. and -10° C. under nitrogenatmosphere and the mixture is stirred at the same temperature for onehour to separate out N-meth-ylmorpholine hydrochloride.

ii) Preparation of Corey reagent (dimethylsulfoxonium methylide)

To a suspension of trimethylsulfoxonium iodide (1.024 g, 4.65 mmol) intoluene (9 ml) and DMSO (1 ml) is added potassium t-butoxide (522 mg,4.65 mmol, 1.0 eq) with stirring under nitrogen atmosphere, and themixture is heated with stirring on an oil bath of 70°-75° C. for 30minutes Orange crystals turns to grayish white crystals.

The carbonic anhydride solution obtained in the above step i) is chargedin a dropping funnel with a cotton stopper. The solution is dropwiseadded to the Corey reagent prepared in the step ii) from the funnel withstirring and ice-cooling under nitrogen atmosphere over 10 minutes andthe mixture is stirred at room temperature for one hour. The mixture isfiltered and the filtrate is extracted with water (10 ml×3). The aqueouslayer is extracted with dichloromethane (10 ml×4). Each extract iswashed with water, dried over MgSO₄, and concentrated to dryness invacuo to obtain 600 mg of crude product. Chromatography (SiO₂ : 40 g,3.5% MeOH/CH₂ Cl₂) of the crude product gives the aimed ylide compound[38a] (554 mg, 85%) as an oil.

To a solution of the ylide [38a] (3.16 g, 9.83 mmol) in dichloroethane(26 ml) is added 2N HCl/ethyl acetate (4.92 ml, 9.84 mmol) with stirringat -10° C. and the mixture is stirred for one hour. The mixture iswarmed on an oil bath of 100° C. Although precipitates (HCl additionproduct) separate out after two minutes, they redissolve after 3.5minutes. When the solution becomes turbid after 6 minutes, the solutionis cooled immediately to terminate the reaction and the reaction mixtureis subjected to silica gel chromatography (SiO₂ : 15 g, AcOEt:CH₂ Cl₂=1:7) to obtain chloromethyl ketone [36a] (2.308 g, 84%) as a crystalsubstance.

A suspension of the above product [36a] (2.308 g, 8.25 mmol), HCSNH₂(1.26 g, 20.62 mmol, 2.5 eq) and CaCO₃ (2.475 g, 24.75 mmol, 3 eq) indichloroethane (23 ml), is stirred at room temperature for 15 hoursunder nitrogen atmosphere. After addition of NaI (62 mg, 0.414 mmol,0.05 eq), the mixture is stirred for additional two hours. Insolublematerials are filtered off and washed with dichloromethane. The filtrateand washings are combined and subsequently washed with saturated aqueoussodium bicarbonate, 1N NaOH, and H₂ O (×2). Chromatographic treatment ofthe solution in the same manner as described in the foregoing process a)provides (4-thiazolyl)-L-alanine derivative [37a] (1.878 g, 80%) as anoil.

To a solution of the above compound [37a] (3.16 g, 11.04 mmol) inmethanol (6 ml) is added with stirring and ice-cooling 1N LiOH (13 ml,13 mmol, 1.18 eq) and the mixture is stirred at room temperature for onehour. Similar procedure as disclosed in the process a) provides crudeproduct [8b] (2.9 g, 97%) Recrystallization of the product from ethylether/n-hexane gives pure product [8b] (2.6 g, 88% as colorless crystalsm.p. 110°-112° C. [α]_(D) =-4.8 (c=2.0; MeOH; 25° C.)

PREPARATION 60 AND 61

N-sulfamylamino acids [12] listed in Table 4 are prepared from thecompounds [30] in the same manner as disclosed in Preparation 58.

PREPARATION 62 AND 63

2-Substituted (4-thiazolyl)-L-alanines [8] listed in Table 5 areprepared from the compounds [36] in the same manner as disclosed inPreparation 59.

                                      TABLE 4                                     __________________________________________________________________________     ##STR48##                                                                    Compd.                            [10]                                        of                           [32]      [α].sub.D ° C = 1,                                               MeOH                                   Prep. No.                                                                           R.sup.4   R.sup.3   E  Yield %                                                                            Yield %                                                                            (Temp. °C.)                     __________________________________________________________________________    60                                                                                   ##STR49##                                                                               ##STR50##                                                                              Me 88   76   -56.7(25)                              61                                                                                   ##STR51##                                                                               ##STR52##                                                                              Et 82   26                                          __________________________________________________________________________                     Compd.                                                                              [10]                                                                    of                                                                            Prep. No.                                                                           IR ν.sub.max.sup.CHCl.sub.3. cm.sup.-1                                               NMR(δ)                                 __________________________________________________________________________                     60    3480, 3340,                                                                             2.55(2H, m), 2.63(2H, m),                                           3200˜2400,                                                                        3.13(2H, m), 3.20(3H, m),                                           1723(1750)1598,                                                                         3.55(1H, bs), 3.80(1H, dd,                                          1508, 1450, 1395,                                                                       J=4.6, 14Hz), 4.35(1H, dt,                                          1342, 1155, 1111,                                                                       J=4.4, 10Hz), 5.05(1H, d,                                           1070, 848 J=10.2Hz), 7.37(2H, m),                                                       7.57(2H, m), 7.89(2H, m),                                                     8.10(1H, d, J=8.2Hz)                                          61              2.58(6H, s), 2.98(1H, dd,                                                     J=7.8, 13.6Hz), 3.20(1H, dd,                                                  J=5.2, 13.6Hz), 4.24(1H,                                                      dofdd, J=9.6, 7.4, 4.6Hz),                                                    4.90(1H, d, J=10Hz),                                                          4.90(1H, bs), 7.30(5H,                       __________________________________________________________________________                                     m)                                       

                                      TABLE 5                                     __________________________________________________________________________     ##STR53##                                                                             [37]         [8]                                                     Compd.        [α].sub.D °                                                                        [α].sub.D °                      of            C = 1, MeOH       C = 1, MeOH                                   Prep. No.                                                                           M  Yield %                                                                            (temp. ° C.)                                                                   Yield %                                                                            mp, (°C.)                                                                   (temp. °C.)                                                                    IR ν.sub.max .sup.CHCl.sub.3                                               cm.sup.-1                                                                              NMR(δ)                 __________________________________________________________________________    62    CH.sub.3                                                                         42   --      93   135- (C = 2) 3430, 2440(br)                                                   136  -20.4   1700, 1495,                                                           (24)    1435, 1392                                                                    1368, 1160                                                                    1060                                  63    NH.sub.2                                                                         88   -345     87*  156-*                                                                             -4.3*   *3440, 3200,                                                                           *1.50(9H, s), 3.38(2H,                                                        m),                                        (24)         157  (22)    2440(br) 4.64(1H, m),                               -10.1*                    1700, 1565, 1500                                                                       5.15(2H, d, J=6.8Hz),                      (22)                      1455, 1435, 1392                                                                       6.69(1H, s),                                                         1370, 1160                                                                             8.48(1H, s)                                                          1062                                  __________________________________________________________________________     *formyl compound                                                         

PREPARATION 64 ##STR54##

To the aldehyde compound [la] (10.08 g, 39.5 mmol) is added NaHSO₃(10.08 g) in water (70 ml) and the mixture is stirred with ice-coolingfor 16 hours. The resultant solution is stirred at room temperature for4 hours after addition of KCN (6.3 g) in water (16.8 ml) and ethylacetate (137 ml). The ethyl acetate layer is separated from the reactionmixture, washed with saturated aqueous sodium chloride, dried, andconcentrated. The residue is subjected to a column chromatography usingLobar column Size C (CH₂ Cl₂ :acetone=19:1). Resultant product isrecrystallized from hexane to give the aimed product [20a](6.51 g, 58%).

The product [20a] (3.56 g, 12.6 mmol) in anhydrous THF (50 ml) is addeddropwise a suspension of LiA1H₄ (574 mg, 1.2 mol) in anhydrous THF (30ml) with stirring and ice-cooling to over 30 minutes. The mixture isstirred at 0° C. for additional one hour. A small amount of ethylacetate and ice water are added to the mixture to separate out inorganicmaterials. The insoluble materials are filtered, and the filtrate isconcentrated in vacuo and then purified with silica gel chromatography(SiO₂ : 120 g, CH₂ Cl₂ :MeOH:NH₄ OH=80:20:2). The aimed compound [21a](2.21 g, 61%) is thus obtained.

To a solution of the compound [21a] (12.49 g, 43.6 mmol) in anhydrousdichloromethane (200 ml) are added triethylamine (8.8 g, 2.0 eq) andmorpholinosulfonyl chloride (10.1 g, 1.25 eq) and the mixture is stirredat room temperature for 3 hours and concentrated in vacuo. The residueis dissolved in ethyl acetate, washed with water, dried, and evaporateto remove the solvent. The residue is purified with silica gelchromatography (SiO₂ : 200 g, CH₂ Cl₂ :MeOH:NH₄ OH=90:10:1). The aimedcompound [23a] (18.16 g, 95%) is thus obtained.

NMR(δ): 0.70-1.85(13H,m), 1.45(9H,s), 3.02(1H,m), 3.18(5H,m),3.72(6H,m), 4.62(1H,d,J=9.2Hz), 5.58(1H,bt)

PREPARATION 65-74

The compounds [23] listed in Table 6 are prepared in the manner astaught in Preparation 64.

    TABLE 6      ##STR55##      Compd.  [23] of  yield  Prep. No. R.sup.1 % NMR(δ)      65 NMe.sub.2 97 0.80˜1.90(13H, m), 1.45(9H, s), 2.80(6H, s),     3.08(2H, m), 3.72(2H, m), 4.63(1H, d, J=9.2Hz),    5.48(1H, m)  66      ##STR56##      90 0.70˜1.80(13H, m), 1.37(9H, s), 2.49(1H, bs), 2.82(1H, dt,     J=6.2, 13.5Hz), 3.12(1H, dt,J=7.13Hz), 3.68(2H, m), 4.60(1H, d, J=9.3Hz),      4.47(1H, dd, J=4.6Hz), 8.17(1H, m), 8.79(1H, bd),9.08(1H, bs)  67      ##STR57##      93 0.70˜1.85(13H, m), 1.39(9H, s), 2.90(1H, dt, J=6.1, 13.4Hz),     3.16(1H, dt, J=7.0, 12.9Hz),2.60(1H, m), 3.67(2H, m), 4.57(1H, d,     J=9.2), 5.89(1H, t, J=7Hz), 7.07(1H, dd, J=3.7, 5.0Hz),7.60(2H, m),     6.24(1H, bt)      68     ##STR58##      99 0.65˜1.80(13H, m), 1.32(9H, s), 2.89(2H, bt), 3.55(1H, m),     3.66(1H, m), 4.58(1H, d, J=9.2Hz),6.80(1H, bt), 7.57(1H, dd, J=4.4,     8.4Hz), 7.66(1H, t, J=7.4Hz), 8.07(1H, dd, J=1.0, 8.2Hz),8.29(1H, dd,     J=1.6, 8.4Hz), 8.42(1H, dd, J=1.4, 7.4Hz), 9.05(1H, dd, J=1.6, 4.4Hz)     69      ##STR59##      97 0.70˜1.80(13H, m), 1.37(9H, s), 2.58(1H, bd, J=5Hz), 2.80(1H,     dt, J=6.2, 13.6Hz), 3.08(1H, dt,J=6.5, 13.6Hz), 3.65(2H, m), 4.56(1H, d,     J=9.2Hz), 5.82(1H, bt, J=6Hz), 7.53(3H, m),7.85(2H, m)      70     ##STR60##      72 0.75˜1.87(13H, m), 1.45(9H, s), 1.98(1H, bs), 2.52(4H, m),     2.86(2H, m), 3.17(4H, m),3.73(6H, m), 4.62(1H, d, J=9.4Hz), 5.63(1H, bt)       71     ##STR61##      36 0.75˜1.88(13H, m), 1.45(9H, s), 2.03(2H, m), 2.49(6H, m),     3.13(4H, m), 3.72(6H, m), 4.65(1H, d,J=9.1Hz), 5.82(1H, bt)      72     ##STR62##      75 0.75˜1.90(13H, m), 1.44(9H, s), 2.29(6H, s), 2.80(2H, m),     3.16(5H, m), 3.64(2H, m), 4.66(1H, d,J=9.6Hz)      73 Me 97 0.75˜1.85(13H, m), 1.45(9H, s), 2.85(1H, bs), 2.96(3H,     s), 3.14(2H, m), 3.72(2H, m), 4.65(1H, d,    J=9.4Hz), 5.53(1H, bt)  74      ##STR63##      98 0.94(3H, t, J=7.2Hz), 0.80˜1.95(17H, m), 1.45(9H, s), 2.76(1H,     bs), 3.00(2H, m), 3.16(2H, m),3.70(2H, m), 4.63(1H, d, J=9Hz), 5.44(1H,     t, J=7Hz)

PREPARATION 75 ##STR64##

A mixture of the compound [23a] (18.16 g, 41.6 mmol), THF (150 ml), and6N HCl (150 ml) is stirred at room temperature for o4 hours. Thereaction mixture is made alkaline with Na₂ CO₃ and saturated aqueousNaHCO₃ and extracted with a mixture of dichloromethane and methanol(9:1). The organic layer is dried and evaporated to dryness in vacuo.The residue is subjected to silica gel column chromatography (SiO₂ : 100g, CH₂ Cl₂ : MeOH:NH₄ OH=80:20:2). The compound [24a] (14.0 g,quantitative amount) is thus obtained.

To a solution of the above compound [24a] (14.0 g, 41.6 mmol) inacetonitrile (200 ml) are added 4-thiazolyl-L-alanine (8b] (12.09 g, 1.1eq) and HOBt (7.04 g, 1.25 eq) with ice-cooling. To the mixture is addedDCC (11.18 g, 1.3 eq) and the resulting mixture is stirred for one hourat 0° C. and one hour at room temperature. The reaction mixture isfiltered after addition of ethyl acetate and the filtrate isconcentrated in vacuo. The residue is subjected to silica gel columnchromatography (SiO₂ : 600 g, CH₂ Cl₂ :MeOH:NH₄ OH=90:10:1) to give theproduct [25a] (24.5 g, quantitative amount).

NMR(δ): 0.70-1.80(13H,m), 1.45(9H,s), 2.45(1H,bs), 2.98(2H,m),3.18(4H,m), 3.30(2H,m), 3.75(5H,m), 4.02(1H,m), 4.46(1H,ddd,J=6.4Hx3),5.72(1H,bt,J=6.6Hz), 6.16(1H,d,J=6.4Hz), 6.36(1H,d,J=9.2Hz),7.15(1H,d,J=1.8Hz), 8.82(1H,d,J=2Hz)

PREPARATION 76-86

Compounds [25] listed in Table 7 are prepared according to the proceduredisclosed in Preparation 75.

    TABLE 7      ##STR65##      Compd.    of   [25] Prep. No. R.sup.1 R.sup.2 Yield % NMR(δ)           76 NMe.sub.2      ##STR66##      90 0.70˜1.80(13H, m), 1.45(9H, s), 2.79(6H, s), 2.95(2H, m),     3.29(2H, m), 3.73(1H, m),4.01(1H, m), 4.48(1H, ddd, J=6.6Hz), 5.58(1H,     bt), 6.15(1H, d, J=7Hz), 6.39(1H, d,J=10Hz), 7.15(1H, d, J=1.8Hz),     8.82(1H, d, J=2Hz)      77     ##STR67##      ##STR68##      94 0.65˜1.75(13H, m), 1.39(9H, s), 2.80(1H, dt, J=6.4, 13.6Hz),     3.00(1H, dt,J=6.6, 13.7Hz), 3.19(2H, d, J=5.6Hz), 3.70(1H, dt, J=2.3,     6.7Hz), 3.99(1H, m),4.46(1H, ddd, J=6Hz), 6.05(1H, d, J=6.3Hz), 6.55(2H,     m), 7.11(1H, d, J=1.8Hz),7.45(1H, m), 7.80(1H, dd, J=4.24Hz), 8.20(1H,     d, J=7Hz), 8.77(1H, d, J=2Hz),9.08(1H, bs)      78     ##STR69##      ##STR70##      99 0.65˜2.00(13H, m), 1.43(9H, s), 2.81(1H, dt, J=6.3, 13.5Hz),     2.99(1H, dt,J=6.9, 13.5Hz), 3.24(2H, m), 3.66(1H, dd, J=2.4, 6.8Hz),     3.97(1H, m), 4.45(1H, ddd,J=6.5Hz×3), 6.02(1H, d, J=6.9Hz),     6.22(1H, bt), 6.39(1H, d, J=9.3Hz), 7.10(2H, m),7.58(2H, m), 8.75(1H, d,     J=1.8Hz)      79     ##STR71##      ##STR72##      96 0.55(13H, m), 1.43(9H, s), 2.79(2H, m), 3.11(1H, dd, J=5.7, 14.7Hz),     3.22(1H, dd,J=5.4, 14.7Hz), 3.65(1H, m), 3.84(1H, m), 4.32(1H, ddd,     J=6.6Hz×3), 6.09(1H, d,J=6Hz), 6.27(1H, d, J=9.4Hz), 6.78(1H, t,     J=6.2Hz), 7.02(1H, d, J=8Hz),7.56(1H, dd, J=4.3, 8.4Hz), 7.65(1H, t,     J=7.4Hz), 8.06(1H, dd, J=1.4, 8.3Hz),8.27(1H, dd, J=1.8, 8.4Hz),     8.41(1H, dd, J=1.4, 7.3Hz), 8.69(1H, d, J=1.9Hz),9.04(1H, dd, J=1.7,     4.2Hz)      80     ##STR73##      ##STR74##      99 0.67˜2.00(13H, m), 1.43(9H, s), 2.74(1H, dt, J=6.9, 13.5Hz),     2.94(1H, dt, J=6.8,13.5Hz), 3.18(1H, dd, J=6.3, 14Hz), 3.27(1H, dd,     J=5.7, 14Hz), 3.62(1H, dt, J=2.6,6.8Hz), 3.95(1H, m), 4.41(1H, ddd,     J=6.6Hz×3), 5.95(1H, bt), 6.05(1H, d, J=6.8),6.29(1H, d, J=9.3Hz),     7.07(1H, d, J=1.9Hz), 7.52(3H, m), 7.86(2H, m), 8.73(1H, d,J=2.0Hz)  81      ##STR75##      ##STR76##      99 0.63˜1.78(13H, m), 1.45(9H, s), 2.14(1H, bs), 2.52(4H, bt,     J=4.6Hz), 2.86(2H, t,J=7Hz), 3.05(2H, bt, J=6Hz), 3.14˜3.40(4H,     m), 3.66(1H, m), 3.73(4H, m),4.00(1H, m), 4.42(1H, ddd, J=6.2Hz),     5.80(1H, bt), 6.24(1H, d, J=6.6Hz), 6.31(1H, d,J=9.4Hz), 7.14(1H, d,     J=2Hz), 8.81(1H, d, J=2Hz)      82     ##STR77##      ##STR78##      99 0.70˜1.80(13H, m), 1.45(9H, s), 2.01(2H, m), 2.49(6H, m),     3.08(4H, m), 3.30(2H, m),3.72(5H, m), 4.00(1H, m), 4.43(1H, ddd,     J=6.6Hz×3), 5.88(1H, bt), 6.24(1H, d,J=6.6Hz), 6.52(1H, d,     J=9.6Hz), 7.15(1H, d, J=1.8Hz), 8.82(1H, d, J=1.8Hz),      83     ##STR79##      ##STR80##      77 0.60˜1.80(13H, m), 1.45(9H, s), 2.29(6H, s), 2.81(2H, t,     J=6.2Hz), 3.04(2H, d,J=6.6Hz), 3.18(2H, m), 3.25(1H, dd, J=5.6, 14.6Hz),     3.34(1H, dd, J=5.4, 14.6Hz),3.65(1H, dt, J=2.4, 6.2Hz), 3.98(1H, m),     4.45(1H, ddd, J=6.6Hz), 6.22(1H, d,J=6.6Hz), 6.40(1H, d, J=9.6Hz),     7.14(1H, d, J=2Hz), 8.81(1H, d, J=2Hz)      84 Me     ##STR81##      75 0.70˜1.80(13H, m), 1.45(9H, s), 2.96(6H, s), 3.03(2H, m),     3.30(2H, m), 3.70(1H, m),4.02(1H, m), 4.46(1H, ddd, J=6.6Hz×3),     5.72(1H, bt), 6.21(1H, d, J=6.6Hz),6.39(1H, d, J=9.6Hz), 7.15(1H, d,     J=1.6Hz), 8.82(1H, d, J=1.8Hz)      85     ##STR82##      ##STR83##      83 0.95(3H, t, J=7.2Hz), 0.65˜1.88(17H, m), 1.45(9H, s), 3.00(5H,     m), 3.30(2H, m),3.68(1H, dt, J=2.3, 6.6Hz), 4.01(1H, m), 4.45(1H, ddd,     J=6.2Hz×3), 5.56(1H, bt),6.18(1H, d, J=6.6Hz)6.35(1H, d, J=9.6Hz),     7.14(1H, d, J=1.8Hz), 8.81(1H, d,J=2.0Hz)      86     ##STR84##      ##STR85##      99 0.65˜1.75(13H, m), 1.43(9H, s), 2.64(3H, s), 2.74(1H, dt,     J=6.3, 13.6Hz), 2.96(1H,dt, J=6.8, 13.4Hz), 3.10(2H, m), 3.61(1H, dt,     J=3.6, 6Hz), 3.96(1H, m), 4.34(1H, ddd,J=5.8Hz), 5.90(1H, m), 6.00(1H,     d, J=6.2Hz), 6.32(1H, d, J=9.2Hz), 6.82(1H, s),7.52(3H, m), 7.86(2H, dd,     J=1.6, 7.8Hz)

EXAMPLE 1

3-t-Butylsulfonyl-2(S)-phenylmethylpropionyl-His-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-pyridyl)butylamide [Ia]

1)His(Ts)-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-(4-pyridyl)butylamide[11a] ##STR86##

Boc-His(Ts) 1(S)-cyclohexylmethyl-2(S),hydroxy-4-oxo-4-(4-pyridyl)butylamide [10a] (1.31 g, 1.96 mmol) preparedin Preparation 21 is dissolved in anisole (13 ml). To the solution isadded trifluoroacetic acid (13 ml) with stirring and ice-cooling and themixture is stirred at room temperature for one hour. After evaporationof the reaction mixture to dryness in vacuo, ice is added to the residueand the mixture is washed with ethyl ether. The aqueous layerneutralized with 3N NaOH and adjusted to pH8 by addition of powdered Na₂CO₃ is extracted with dichloromethane three times and finally extractedwith a mixture of dichloromethane and methanol (10:1). The organic layeris washed with saturated aqueous sodium chloride, dried over MgSO₄ andevaporated to dryness in vacuo. The residue is purified with silica gelchromatography (CH₂ Cl₂ :MeOH=95:5) to obtain the aimed crude product(850 mg, 73%). Recrystallization of the crude product from ethyl acetateprovides the title compound [11a] (750 mg, 65%) as a needle crystal.m.p.161°-162° C.

NMR(δ): 0.75-1.80(13H,m), 1.98(1H,br.s), 2.44(3H,s),2.73(1H,dd,J=14.8,8.2Hz), 2.95.sup.˜ 3.24(3H,m),3.65(1H,dd,J=8.4,4.2Hz), 4.02(1H,m), 4.27(1H,m), 7.12(1H,d,J=1.2Hz),7.36(2H,d,J=7.8Hz), 7.53(1H,d,J=10Hz), 7.70(2H,m), 7.81(2H,d,J=8.4Hz),7.92(1H,d,J=1.4Hz), 8.79(2H,m)

IR νmax(CHCl₃)cm⁻¹ :3680, 3340, 1690, 1654, 1602, 1593, 1515, 1475, 1450

Elemental analysis (as C₂₉ H₃₉ N₅ O₆ S):

Calcd.: C:59.01; H:6.75; N:11.87; S:5.43:

Found: C:59.12; H:6.69; N:11.68; S:5.21:

2) 3-t-Butylsulfonyl-2(S)-phenylmethylpropionyl-His(Ts)1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-(4-pyridyl)butylamide [13a]##STR87##

To a solution of the ketone compound [11a] (334 mg, 0.57 mmol) indichloromethane (1 ml) are added3-t-butylsulfonyl-2(S)-phenylmethylpropionic acid (220 mg, 0.76 mmol,1.3 eq), N-methylmorpholine (77 mg, 0.76 mmol, 1.3 eq), and then DEPC(124 mg, 0.76 mmol, 1.3 eq) and the mixture is stirred at roomtemperature for four hours. The reaction mixture is evaporated todryness in vacuo and subjected to silica gel chromatography (CH₂ Cl₂:MeOH=95:5) to obtain the title compound [13a] (418 mg, 89%) ascolorless powders.

NMR δ: 0.70-2.10(14H,m), 1.33(9H,s), 2.43(3H,s), 2.70-3.28(8H,m),3.45(1H,dd,J=12.9,9.4Hz), 4.00(1H,m), 4.18(1H,m),4.53(1H,ddd,J=5.8,5.8,5.8Hz), 6.34(1H,d,J=10Hz), 7.17(1H,d,J=1.2Hz),7.22(5H,m), 7.34(2H,d,J=8.4Hz), 7.81(2H,d,J=8.5Hz), 7.85(1H,d,J=1.2Hz),7.75(2H,d,J=6.0Hz), 8.81(2H,d,J=5.9Hz)

IR νmax(CHCl₃) cm⁻¹ :3680, 3470, 3370, 1665, 1600, 1520, 1450, 1172,1112, 1075

3) 3-t-Butylsulfonyl-2(S)-phenylmethylpropionyl-His1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-(4-pyridyl)butylamide [Ia]##STR88##

To a solution of the protected compound [13a] (740 mg, 0.89 mmol)obtained in the above step 2) in DMF (4 ml) is added pyridiniumhydrochloride (1030 mg, 8.87 mmol, 10.0 eq) and the mixture is stirredat room temperature for two hours. The reaction mixture is adjusted topH 7-8 by addition of ice and 4% aqueous NaHC03 and extracted threetimes with dichloromethane. The organic layer is washed with saturatedaqueous sodium chloride, dried over MgSO₄, and concentrated to drynessin vacuo. The residue is purified with silica gel chromatography (CH₂Cl₂ :MeOH:concNH₄ OH=950:50:1) to obtain the title compound [Ia] (543mg, 90%). Trituration of the residue with diisopropyl ether givescolorless powders.

NMR δ: 0.67-1.83(13H,m), 1.33(9H,s), 2.86(1H,d,J=13.5,8.4Hz),2.97(1H,dd,J=13.0,9.8Hz), 3.10(5H,m), 3.26(1H,m),3.56(1H,dd,J=13.0,9.8Hz), 4.02(1H,m), 4.20(1H,m),4.56(1H,ddd,J=6.3,6.3,6.3Hz), 6.44(1H,d,J=10Hz), 6.90(1H,s), 7.24(4H,m),7.48(1H,s), 7.46(1H,bs), 7.70(2H,m), 8.78(2H,m)

[α]_(D) =-22.5° (C=1.0; MeOH; 23° C.) IR

νmax(CHCl₃)cm⁻¹ :3460, 3360(br), 1662(1690sh), 1603, 1496, 1450, 1410,1115

Elemental analysis (as C₃₆ H₄₉ N₅ O₆ S3/4H₂ O):

Calcd.: C:62.36; H:7.34; N:10.10; S:4.62:

Found: C:62.42; H:7.33; N:10.21; S:4.49:

EXAMPLES 2-52

The same procedure as disclosed in the steps 1) and 2) in Example 1 isrepeated using, as the starting material, the compounds [10] prepared inforegoing Preparations 21-58, and the compounds [11] and [13] listed inTables 8 (compound [11]) and 9 (compound [13]) are obtained. Thecompounds [13] (for example, compound [13] of No. 23) wherein R¹ or R²is not protected correspond to the compounds (I) of the invention. Wherethe substituent R² is protected, the compounds [13] are deprotectedaccording to the procedure as disclosed in Step 3) in Example 1 toobtain the final products (I), which are listed in the following Table10.

    TABLE 8      ##STR89##       Comp.   [11] of   Yield % [α].sub.D ° (C =      1.0, CHCl.sub.3)  Elemental analysis Ex. No. R.sup.1 R.sup.2' m.p.     (°C.) (°C.) IR νmax cm.sup.-1 or NMR (δ) Calcd.     Found       2 phenyl      ##STR90##      81126-127 -49.1(23.5) 3560, 3360, 1666,1598, 1580, 15111450, 1382,     1172, 1075 C: 63.58H: 6.76N: 9.89S: 5.66 C: 63.34H: 6.67N: 9.84S: 5.67     3 o-fluorophenyl      ##STR91##      67  3600, 3460(br), 1670,1610, 1598, 1510, 1480,1450, 1383, 1170, 1075     oil      4 m-methoxyphenyl     ##STR92##      55  0.70˜1.83(13H, m), 2.05(3H, bs), 2.44(3H, s), 2.72(1H, dd,     J=8.16Hz),2.98(1H, dd, J=10, 18Hz), 3.07(1H, dd, J=6.16Hz), 3.18(1H, dd,     J=3, 18Hz)4.66(1H, dd, J=4.8Hz), 3.85(3H, s), 4.02(1H, m), 4.24(1H, m),     7.17(1H, s)7.17(1H, m), 7.30˜7.60(3H, m), 7.35(2H, d, J=8.0Hz),7.80     (2H, d, J=8.4Hz), 7.91(1H, d, J=1.4Hz) oil      5 p-methylphenyl     ##STR93##      43  3360, 1668, 1608, 1570, 1510,1450, 1385, 1172, 1092, 1075 oil  6     2,4-difluoro-phenyl      ##STR94##      71 -43.9(23.5) 3580, 3360, 1665, 1612, 1595,1510, 1498, 1475, 1383,     1172,1075, 970 C: 59.78H: 6.02N: 9.30S: 5.32F: 6.31 C: 59.53H: 6.04N:     9.42S: 5.56F: 6.38      7 1-naphthyl     ##STR95##      49  3400(br), 1665, 1599, 1575,1510, 1450, 1386, 1190, 1174,1094, 1080,     909 oil       Compd.   [11] of    [α].sub.D °   Ex. No. R.sup.1     R.sup.2' Yield % (C = 1.0, CHCl.sub.3) (°C.) mp (°C.) IR     νmax cm.sup.-1 or NMR(δ)       8 3-thienyl     ##STR96##      70   3680, 3360(br), 3120, 1665,1598, 1510, 1475, 1450, 1382,1172, 1076      9 2-thiazolyl     ##STR97##      52   0.73˜1.83(13H, m), 2.33(2H, bs), 2.44(3H, s), 2.76(1H, dd,     J=7.15Hz),3.07(1H, dd, J=3.6, 14.6Hz), 3.18˜3.38(2H, m), 3.68(1H,     m), 4.02(1H, m),4.25(1H, m), 7.14(1H, s), 7.35(2H, d, J=8.0Hz), 7.51(1H,     d, J=9.0Hz),7.69(1H, d, J=3.0Hz), 7.80(2H, d, J=8.4Hz), 7.95(1H, d,     J=1.2Hz),8.01(1H, d, J=3.0Hz)      10 m-fluorophenyl     ##STR98##      66   3360, 1670, 1590,1510, 1445, 1382,1170, 1090, 1075      11 p-fluorophenyl      ##STR99##      57 -45.8(24.0) 128˜130 3360, 3500(br), 1665, 1600, 1508, 1475,     14501095, 1075      12 2,6-difluoro-phenyl     ##STR100##      53 -23.9(24.0)  3368, 1698, 1665, 1624, 1598, 1512, 1420, 1385, 1279,     1190, 1174, 1094,1077, 1018      13 o-methoxyphenyl     ##STR101##      25   0.70˜1.85(13H, m), 2.20(3H, bs), 2.44(3H, s), 2.74(1H, dd,     J=8.15Hz),2.95(1H, dd, J=10, 17Hz), 3.10(1H, dd, J=15.5Hz), 3.26(1H, dd,     J=17, 3Hz)3.69(1H, dd, J=5, 10Hz), 3.88(3H, s), 3.99(1H, m), 4.18(1H,    6     m),.98(2H, m), 7.12(1H, s), 7.35(2H d, J=8Hz), 7.50(1H, m),7.72(1H, dd,     J=7.5, 2Hz), 7.81(2H, d, J=8Hz), 7.92(1H, s)       Compd.    of   [11] Ex. No. R.sup.1 R.sup.2' Yield % mp (°C.)     IR νmax cm.sup.-1 or NMR(δ)       14 o-chlorophenyl      ##STR102##      75  0.70˜1.82(13H, m), 2.40(3H, s), 2.44(3H, s), 2.72(1H, dd,     J=8.15, 8Hz),3.00(1H, dd, J=17.5, 10Hz), 3.07(1H, dd, J=15.5Hz),     3.17(1H, dd, J=17.5,4Hz), 3.65(1H, dd, J=10.5Hz), 3.98(1H, m), 4.23(1H,     m), 7.11(1H, s),7.25˜7.58(6H, m), 7.81(2H, d, J=8.4Hz), 7.91(1H,     d, J=1.4Hz)      15 m-cyanophenyl     ##STR103##      79  3360, 2236, 1666, 1514, 1498, 1450, 1386, 1189, 1174, 1094, 1078,     909      16 o-methyl-sulfonyl-aminophenyl     ##STR104##      38  3368, 1657, 1607, 1578, 1496, 1452, 1386, 1340, 1189, 1173, 1094,     1078,968, 909      17 p-trifluoro-methylphenyl     ##STR105##      53 113˜115 3360, 1670, 1600, 1510, 1450, 1410, 1385, 1325, 1180,     1135, 1065       Compd.    of   [11] Ex. No. R.sup.1 R.sup.2' Yield % NMR (δ)       18 m-morpholino-carbonyloxy-phenyl      ##STR106##      81 0.73˜2.20(13H, m), 2.44(3H, s), 2.75(1H, dd, J=14.8, 8.6Hz),2.9     3˜3.24(3H, m), 3.5˜3.82(8H, m), 4.02(1H, m), 4.23(1H,     m),7.13(1H, d, J=1.0Hz), 7.35(2H, d, J=8.0Hz), 7.35(1H, m),7.47(1H, t,     J=7.5Hz), 7.60(1H, d, J=10Hz), 7.67(1H, m),7.81(2H, d, J=8.4Hz),     7.81(1H, m), 7.91(1H, d, J=1.4Hz)  19 m-morpholino-carbonylphenyl      ##STR107##      41 0.70˜1.85(13H, m), 2.28(3H, bs), 2.44(3H, s), 2.75(1H, dd,     J=8.6, 14.8Hz), 2.95·3.27(3H, m), 3.30˜3.94(8H, m),     3.68(1H, dd, J=8.4, 4.2Hz), 4.02(1H, m), 4.26(1H, m), 7.14(1H, d,     J=1.4Hz),7.36(2H, d, J=8Hz), 7.47˜7.69(2H, m), 7.81(2H, d,     J=8.4Hz),7.93(1H, d, J=1.2Hz), 7.98(1H, d, J=1.6Hz), 8.00(1H, m)  20     3,4-methylene-dioxyphenyl      ##STR108##      74 0.70˜2.15(13H, m), 2.44(3H, s), 2.73(1H, dd, J=14.4, 8.4Hz),2.9     1(1H, dd, J=17.8, 9.6Hz), 3.09(1H, dd, J=14.6, 4.2Hz),3.13(1H, dd,     J=18.4Hz), 3.67(1H, dd, J=8.6, 3.8Hz), 4.00(1H, m),4.20(1H, m), 6.05(2H,     s), 6.84(1H, d, J=8.2Hz), 7.12(1H, d, J=1.0Hz),7.36(2H, d, J=8.0Hz),     7.40(1H, d, J=1.6Hz), 7.53(1H, dd, J=8.2, 1.6Hz),7.81 (2H, d, J=8.2Hz),     7.92(1H, d, J=1.4Hz)      21 cyclohexyl     ##STR109##      68 0.70˜1.89(23H, m), 2.13(3H, bs), 2.33(1H, m), 2.45(1H,     m),2.47(1H, dd, J=17.6, 9.4Hz), 2.66(1H, dd, J=15.2, 6Hz),2.71(1H, dd,     J=14, 9.4Hz), 3.07(1H, dd, J=14.8, 3.6Hz),7.12(1H, d, J=1.2Hz), 7.37(2H,     d, J=8.4Hz), 7.48(1H, d, J=10Hz),7.82(2H, d, J=8.4Hz), 7.94(1H, d,     J=1.4Hz)      22 p-methoxyphenyl     ##STR110##      51 0.76˜2.20(13H, m), 2.44(3H, s), 2.72(1H, dd, J=8.6, 15Hz),2.93(     1H, dd, J=9.6, 17.6Hz), 3.94(1H, dd, J=3.6, 15Hz),3.17(1H, dd, J=2.4,     17.6Hz), 3.67(1H, dd, J=4, 8.6Hz), 3.88(3H, s),4.02(1H, m), 4.23(1H, m),     6.93(2H, d, J=9Hz), 7.27(1H, s),7.36(2H, d, J=8.2Hz), 7.52(1H, d,     J=9.6Hz), 7.81(1H, d, J=8.4Hz),7.91(2H, d, J=9Hz), 7.92(1H, d , J=1.8Hz)       Compd.    of   [11] Ex. No. R.sup.1 R.sup.2 Yield % NMR(δ)       23 phenyl      ##STR111##      70 0.7˜2.05(13H, m), 2.96(1H, dd, J=18.9, 4Hz),3.15(1H, dd,     J=14.2, 7.8Hz), 3.21(1H, dd, J=18, 2.6Hz),3.36(1H, dd, J=14.2, 4.2Hz),     3.80(1H, dd, J=7.8, 4.4Hz), 4.04(1H, m),4.24(1H, m), 7.11(1H, d,     J=1.6Hz), 7.41˜7.63(3H, m),7.94(2H, m), 8.75(1H, d, J=1.8Hz) (mp.     106˜107° C.)      24 4-pyridyl     ##STR112##      70 0.70˜ 1.85(13H, m), 2.04(3H, m), 3.02(1H, dd, J=18, 8.6Hz),     3.10˜3.26(2H, m), 3.36(1H, dd, J=14.4, 4.2Hz), 3.82(1H, dd, J=7.6,     4.4Hz),4.02(1H, m), 4.26(1H, m), 7.13(1H, d, J=1.6Hz), 7.59(1H, d,     J=10Hz),7.71(2H, dd, J=4.6, 1.6Hz), 8.76(1H, d, J=2Hz),8.82(2H, dd,     J=4.6, 1.6Hz) (mp. 118˜120° C.)      25 3-thienyl     ##STR113##      72 0.70˜1.87(13H, m), 2.28(3H, bs), 2.89(1H, dd, J=17.6, 9.4Hz),3.     10(1H, dd, J=17.6, 2.7Hz), 3.14(1H, dd, J=14.3, 7.8Hz),3.35(1H, dd,     J=14.3, 4.1Hz), 3.78(1H, dd, J=7.8, 4.3Hz), 4.00(1H, m),4.20(1H, m),     7.12(1H, d, J=2.0Hz), 7.31(1H, dd, J=5.1, 2.9Hz),7.52(1H, dd, J=5.1,     1.2Hz), 7.57(1H, s), 8.08(1H, dd, J=2.9, 1.2Hz),8.75(1H, dd, J=2Hz)  26     cyclohexyl      ##STR114##      69Mp.90-93 0.70˜1.90(24H, m), 1.98(3H, bs), 2.32(1H, m), 2.45(1H,     dd, J=9.8, 1.8Hz),2.66(1H, dd, J=18, 2.8Hz), 3.15(1H, dd, J=14, 7.4Hz),3.     35(1H, dd, J=14.4, 3.8Hz), 3.80(1H, dd, J=7.4, 4.2Hz), 3.91(1H, m),4.02(1     H, m), 7.13(1H, d, J=1.6Hz), 7.50(1H, d, J=9.8Hz),8.78(1H, d, J=1.8Hz)          [11] Compd.    [α].sub.D.sup.°  of    (C =      1, CHCl.sub.3) Ex. No. R.sup.1 R.sup.2 Yield % (Temp. °C.)     NMR(δ)       27 m-2-(N-morpholino)-ethoxyphenyl      ##STR115##      76 -46.8(23.5) 0.70˜2.10(13H, m), 2.59(4H, t, J=4.7Hz), 2.82(2H,     t, J=5.7Hz), 2.94(1H, dd,J=9.5, 17.9Hz), 3.15(1H, dd, J=7.6, 14.6Hz),     3.18(1H, dd, J=2.5, 17.9Hz), 3.34(1H, dd,J=4.1, 14.6Hz), 3.74(4H, t,     J=9.3Hz), 3.74(1H, m), 4.02(1H, m), 4.15(2H, t, J=8.7Hz),4.22(1H, m),     7.11(1H, br, s), 7.15(1H, d, J=2.7), 7.36 (1H, t, J=8.2), 7.45˜7.62     (2H, m),8.75(1H, d, J=1.1Hz)  28 m-(N-formyl)-methylamino-phenyl      ##STR116##      73  0.77˜1.85(13H, m), 2.40(2H, m), 3.02(1H, dd, J=9.0, 17.9Hz),     3.17(3H, m), 3.34(3H, s),3.35(1H, m), 3.60(1H, dd, J=4.3, 7.8Hz),     4.03(1H, m), 4.25(1H, dt, J=2.1, 8.2Hz),7.13(1H, d, J=2.0Hz), 7.38(1H,     ddofd, J=8.0, 1.2, 2.3Hz), 7.52(1H, t, J=7.52Hz),7.59(1H, d, J=9.7Hz),     7.79(2H, m), 8.52(1H, s), 8.75(1H, d, J=2.0)  29 N-methyl-3-pyrrolyl      ##STR117##      69 -57.6(24) 0.70˜2.00(13H, m), 2.65(1H, dd, J=9.8, 16.8Hz),     2.94(1H, dd, J=2.4, 17Hz), 3.13(1H, dd,J=7.6, 14.4Hz), 3.35(1H, dd,     J=4.2, 14.6Hz), 3.69(3H, s), 3.77(1H, dd, J=4.2, 8Hz),3.99(1H, m),     4.13(1H, dt, J=9.6, 2Hz), 6.56(1H, s), 6.57(1H, s), 7.11(1H, d, J=1.8Hz),7     .27(1H, s), 7.53(1H, d, J=9.6Hz), 8.76(1H, d, J=2Hz)      30 N-morpholino-methyl      ##STR118##      52      31 N-pyperidino-methyl     ##STR119##      36      32 4-pyridyl     ##STR120##      76  0.76˜1.90(13H, m), 2.35(3H, bs), 2.67(3H, s), 3.14(4H, m),     3.80(1H, dd, J=4.2, 7.8Hz),4.03(1H, m), 4.25(1H, m), 6.88(1H, s),     7.58(1H, d, J=9.6Hz), 7.71(2H, m), 8.81(2H, m)      33 phenyl     ##STR121##      70  0.78˜1.75(13H, m), 3.11(4H, m), 4.07(2H, m), 4.23(1H, m),     6.70(1H, s), 7.41(2H, dd,J=7.8, 15.3Hz), 7.57(1H, t, J=7Hz), 7.88(2H, d,     J=7.2Hz), 8.49(1H, s)  34 4-pyridyl CONH.sub.2 17 35 4-pyridyl SMe 88     0.70˜1.80(13H, m), 2.13(3H, s), 2.73(1H, dd, J=8.2, 13.8Hz),     3.02(1H, dd, J=4, 13.6Hz),      3.09(1H, dd, J=8.6, 15.2Hz), 3.20(1H,     dd, J=3.6, 18.4Hz), 3.58(1H, dd, J=4, 8.4Hz),      4.06(1H, m), 4.28(1H,     m), 7.58(1H, d, J=10Hz), 7.72(2H, m), 8.81(2H, m)

    TABLE 9      ##STR122##       Compd.  [13] of    Yield  Ex. No. R.sup.1 R.sup.4' R.sup.2' % IR     νmax(cm.sup.-1) or NMR(δ)      2 phenyl tert-butyl     ##STR123##      86 0.70˜1.82(13H, m), 1.32(9H, s), 1.93(1H, bs), 2.44(3H,s),     2.75˜3.14(7H, m),3.21(1H, m), 3.48(1H, dd, J=13, 9Hz, 3.98(1H, m),     4.20(1H, m),4.56(1H, ddd, J=6, 6Hz), 6.44(1H, d, J=9.4Hz), 7.13˜7.3     0(6H, m),7.40˜7.63(3H, m), 7.34(2H, d, J=8.4Hz), 7.80(2H, d,     J=8.4Hz),7.89(1H, d, J=1), 7.96(2H, d, J=7.8Hz)   3 o-fluorophenyl     tert-butyl      ##STR124##      73 0.70˜1.80(13H, m), 1.34(9H, s), 2.15(2H, bs), 2.70˜3.15(7     H, m),3.19(1H, m), 3.51(1H, dd, J=9.6, 13.4Hz), 3.97(1H, m), 4.15(1H,    4     m),.58(1H, ddd, J=6.2, 6.2, 6.2Hz), 6.43(1H, d, J=9.0Hz), 7.18(1H,     s),7.05˜7.41(7H, m), 7.34(2H, d, J=8.2Hz), 7.54(1H, m), 7.82(2H,     d, J=8.6Hz),7.87(1H, ddd, J=7.7, 1.9Hz), 7.96(1H, d, J=1.7Hz)   4     m-methoxyphenyl tert-butyl      ##STR125##      93 0.70˜1.82(13H, m), 1.33(9H, s), 2.43(3H, s), 2.77˜3.13(7H     , m),3.20(1H, m), 3.49(1H, dd, J=9, 16Hz), 3.86(3H, s), 3.48(1H,     m),4.18(1H, m), 4.56(1H, ddd, J=7, 7, 7Hz), 6.40(1H, d, J=0.0Hz),7.21(1H,      s), 7.09˜7.40(7H, m), 7.52(2H, m), (2H, d, J=8.4Hz),7.87(1H, d,     J=1.4Hz)      5 p-methylphenyl tert-butyl     ##STR126##      79 3400, 3260, 3140, 1665, 1625, 1605, 1498, 1450, 1370, 1172, 1115,     1030, 1010      6 2,4-difluoro-phenyl tert-butyl     ##STR127##      76 3400(br), 1665, 1600, 1599(sh), 1500, 1475, 1175, 970, 855   7     1-naphthyl tert-butyl      ##STR128##      41 3696, 3416, 1667, 1598, 1509, 1477, 1450, 1385, 1292, 1175, 1117,     1094, 1080      ##STR129##        Compd.  [13] of    Yield  Ex. No. R.sup.1 R.sup.4' R.sup.2' % IR     νmax(cm.sup.-1) or NMR(δ)      8 3-thienyl tert-butyl     ##STR130##      74 3410, 3360(sh), 1665, 1598, 1510, 1385, 1173, 1116, 1093, 1078   9     2-thiazolyl tert-butyl      ##STR131##      81 0.7˜1.82(13H, m), 1.35(9H, s), 2.37(1H, bs), 2.43(3H, s),2.78.a     bout.3.28(8H, m), 3.53(1H, dd, J=9.0, 13.0Hz),3.97(1H, m), 4.18(1H,     m),4.58(1H, ddd, 6.4, 6.4, 6.4Hz), 6.35(1H, d, J=9.0Hz), 7.05(1H, d,     J=6.4Hz),7.20(1H, s), 7.13˜7.40(5H, m), 7.33(2H, d, J=8.4Hz),     7.68(1H, d, J=3.2Hz),7.80(2H, d, J=8.4Hz), 8.00(1H, d, J=1.2Hz),     8.01(2H, d, J=3Hz)      10 m-fluorophenyl tert-butyl     ##STR132##      83 3460, 3360, 3280, 3160, 1665, 1625, 1590, 1500, 1450, 1115, 1032,     1010        Compd.  [13] of    Yield  Ex. No. R.sup.1 R.sup.4' R.sup.2' % IR or     NMR       11 p-fluorophenyl tert-butyl      ##STR133##      71 3410, 3280, 3160, 1665, 1625, 1600, 1509, 1450, 1155, 1115, 1030,     1010      12 2,6-difluoro-phenyl tert-butyl     ##STR134##      97 3420, 1660, 1624, 1599, 1499, 1467, 1459, 1385, 1292, 1189, 1175,     1118, 1093, 1085, 1018      13 o-methoxyphenyl tert-butyl     ##STR135##      79 0.70˜1.80(13H, m), 1.33(9H, s), 2.42(3H, s), 2.78˜3.25(7H     , m), 3.50(1H, dd, J=18, 13Hz), 3.88(3H, s), 3.95(1H, m), 4.10(1H,     m),4.48(1H, ddd, J=6.5, 6.5, 6.5Hz), 6.48(1H, d, J=9Hz), 6.97(2H,     m),7.06˜7.40(9H, m), 7.49(1H, m), 7.73(1H, dd, J=9.2Hz),7.79(2H,     d, J=8Hz), 7.84(1H, s)      14 o-chlorophenyl tert-butyl     ##STR136##      81 0.70˜1.80(13H, m), 1.31(9H, s), 2.40(3H, s), 2.80˜3.22(7H     , m),3.50(1H, dd, J=15.7 5Hz), 3.93(1H, m), 4.09(1H, m), 4.51(1H, dd,     J=6.4,6.4, 6.4Hz), 6.29(1H, d, J=10Hz), 7.03˜10Hz), 7.03˜7.41     (8H, m), 7.53(1H, m),7.78(2H, d, J=8.4Hz), 7.78(1H, d, J=1.4Hz)  15     m-cyanophenyl tert-butyl      ##STR137##      84 3408, 2236, 1668, 1599, 1508, 1478, 1450, 1368, 1291, 1190, 1175,     1117, 1079, 908      16 o-methyl-sulfonyl-aminophenyl tert-butyl     ##STR138##       3420, 1666, 1607, 1578, 1499, 1452, 1387, 1340, 1290, 1174, 1155,     1117, 1079, 968, 909      17 p-trifluoromethyl phenyl tert-butyl     ##STR139##      85 3400˜3200, 3140, 1665, 1625, 1600, 1510, 1450, 1410, 1325,     1175, 1135, 1115, 1065      ##STR140##       Compd.  [13] of    Yield  Ex. No. R.sup.1 R.sup.4' R.sup.2' % IR     νmax(cm.sup.-1) or NMR(δ)       18 m-morpholino-carbonyloxyphenyl tert-butyl      ##STR141##      79 0.70˜1.82(13H, m), 1.90(1H, bs), 1.32(9H, s), 2.43(3H,     s),2.74˜3.30(7H, m)3.49(1H, dd, J=14, 10Hz), 3.52˜3.82(8H,     m), 3.96(1H, m),4.16(1H, m), 4.54(1H, ddd, J=6.2, 6.2, 6.2Hz), 6.40(1H,     d, J=9.4Hz),7.10˜7.40(7H, m), 7.33(2H, d, J=8.2Hz), 7.48(1H, t,     J=7.5Hz), 7.70(1H, m),7.80(2H, d, J=8.4Hz), 7.80(1H, m), 7.89(1H, d,     J=1. 2Hz)      19 m-morpholino-carbonylphenyl tert-butyl     ##STR142##      85 0.7˜1.82(13H, m), 1.32(9H, s), 2.43(3H, s), 2.70˜3.30(8H,      m),3.48(1H, dd, J=9.4, 12.8Hz), 3.30˜3.90(8H, m), 3.99(1H, m),     4.20(1H, m),4.53(1H, ddd, J=6.2, 6.2, 6.2Hz), 6.42(1H, d, J=9.4Hz),     7.08˜7.31(6H, m),7.34(2H, d, J=d, J=8.2Hz), 7.45˜7.68(2H,     m), 7.81(2H, d, J=8.4Hz),7.91(1H, d, J=1.4Hz, 8.05(2H, m)      20 3',4'-methylene-dioxyphenyl tert-butyl      ##STR143##      89 0.7˜1.8(13H, m), 1.9(1H, bs), 1.33(9H, s), 2.44(3H, s),     2.74˜3.30(7H, m),3.50(1H, dd, J=9.2, 13Hz), 3.96(1H, m), 4.16(1H,     m),4.56(1H, ddd, J=6.4, 6.4, 6.4Hz), 6.06(2H, s), 6.40(1H, d, J=9.2Hz),6.     85(1H, d, J=8.2Hz), 7.25(6H, m), 7.34(1H, d, J=8.2Hz),7.45(1H, d,     J=1.6Hz), 7.56(1H, dd, J=8.2, 1.6Hz),7.80(2H, d, J=8. 4Hz), 7.85(1H, d,     J=1.4Hz)      21 cyclohexyl tert-butyl     ##STR144##      86 0.70˜1.90(23H, m), 1.34(9H, s), 2.33(1H, m), 2.44(3H, s),     2.78˜3.27(8H, m), 3.50(1H, dd, J=12.0, 8.4Hz), 3.86(1H, m),     3.96(1H, m),4.54(1H, ddd, J=6.2, 6.2, 6.2Hz), 6.35(1H, d, J=10Hz),     7.13˜7.34(6H, m),7.37(2H, d, J=8.4Hz), 7.82(2H, d, J=8.4Hz),     7.90(1H, d, J=1.4Hz),      22 p-methoxyphenyl tert-butyl     ##STR145##      87 0.72˜(13H, m), 0.90(1H, bs), 1.33(9H, s), 2.43(3H, s),2.78.abou     t.3.12(7H, m), 3.20(1H, m), 3.49(1H, dd, J=9.4, 13.2Hz), 3.88(3H,     s),3.97(1H, dd, J=9.4, 13.2Hz), 3.88(3H, s), 3.97(1H, ddd, J=7.4, 7.4,     7.4Hz),4.17(1H, m), 4.57(1H, ddd, J=6, 6, 6Hz), 6.42(1H, d, J=9.4Hz),6.94     (2H, d, J=9Hz), 7.16˜7.26(6H, m), 7.22(1H, s), 7.34(2H, d,     J=8Hz),7.79(2H, d, J 8.4Hz), 7.84(1H, d, J=1.2Hz, 7.94(2H, d, J=9Hz)      ##STR146##       Compd.  of  [13] ([IA]) Ex. No. R.sup.1  R.sup.2 R.sup.3 X R.sup.4     Yield % NMR(δ)       23 phenyl      ##STR147##      ##STR148##      CH.sub.2      ##STR149##      86 0.7˜1.88(13H, m), 1.32(9H, s), 2.83˜3.55(9H, m),     3.96(1H, m), 4.15(1H, m),4.74(1H, ddd, J=5.6Hzx3), 6.32(1H, d, J=9.8Hz),     7.13(1H, d, J=2Hz), 7.25(5H, m),7.47(2H, t, J=7.8Hz), 7.57(1H, d,     J=8Hz), 7.96(2H, d, J=7.2Hz), 8.65(1H, d,J=2Hz)      24 4-pyridyl     ##STR150##      ##STR151##      CH.sub.2      ##STR152##      86 0.60˜1.80(13H, m), 1.33(9H, s), 1.88(2H, bs), 2.86˜3.50(9     H, m), 3.99(1H, m),4.15(1H, m), 4.66(1H, ddd, J=6Hz×3), 6.33(1H,     d, J=9.2Hz), 7.16(1H, d, J=0.6Hz),7.28(5H, m), 7.65(1H, d, J=6Hz),     7.82(2H, bs), 8.69(1H, d, J=0.6Hz), 8.82(2H, bs)      25 3-thienyl     ##STR153##      ##STR154##      CH.sub.2      ##STR155##      79 0.65˜1.82(13H, m), 1.33(9H, s), 2.82˜3.55(9H, m),     3.95(1H, m), 4.15(1H, m),4.72(1H, ddd, J=6H×3), 6.33(1H, d,     J=9.4Hz), 7.14(1H, d, J=2Hz),7.17˜7.38(6H, m), 7.55(1H, dd, J=5.2,     1.4Hz), 7.55(1H, s), 8.20(1H, dd,J=1.2, 2.8Hz), 8.67(1H, d, J=2Hz)  26     cyclohexyl      ##STR156##      ##STR157##      CH.sub.2      ##STR158##      87 0.7˜2.00(24H, m), 1.35(9H, s), 2.32(1H, m), 2.88˜3.58(9H,      m), 3.83(1H, m),3.92(1H, m), 4.70(1H, ddd, J=5.2Hz×3), 6.30(1H,     d, J=9.8Hz), 7.16(1H, d, J=2Hz),7.27(5H, m), 7.50(1H, d, J=5.8Hz),     8.71(1H, d, J=2.2Hz)      27 m-2-(N-morpholino)ethoxy-phenyl     ##STR159##      ##STR160##      CH.sub.2      ##STR161##       91 0.6˜1.8(13H, m), 2.60(4H, m), 2.84(2H, t, J=11.2Hz), 2.89.abou     t.3.62(9H, m),3.75(4H, m), 3.95(1H, ddd, J=7.8Hz×3), 4.18(2H, t,     J=5.4Hz), 4.18(1H, m),4.73(1H, ddd, J=5.2Hz×3), 6.32(1H, d,     J=9.4Hz), 7.14(1H, d, J=2Hz), 7.14(1H, m),7.22˜7.56(3H, m),     8.67(1H, d, J=2Hz)      28 m-(N-form-yl)methyl-amino-phenyl     ##STR162##      ##STR163##      NH      ##STR164##      91 0.60˜1.78(13H, m), 2.51(2H, m), 2.84(4H, m), 3.17(2H, m),     3.37(3H, s),3.40(5H, m), 3.54(1H, dd, J=4.1, 10Hz), 3.96(2H, m),     4.14(1H, m), 4.74(1H, m),5.20(1H, d, J=5.7Hz), 6.60(1H, d, J=6.6Hz),     7.15(1H, d, J=1.9Hz), 7.34(5H, m),7.53(1H, t, J=8.9Hz), 7.89(2H, m),     8.61(1H, s), 8.84(1H, d, J=2.1Hz),9.26(1H, d, J =7.2Hz)      29 N-methyl-pyrrolyl      ##STR165##      ##STR166##      CH.sub.2      ##STR167##      85 0.70˜1.80(13H, m), 2.63(1H, dd, J=9.6, 16.8Hz), 2.80(1H, dd,     J=2.5, 16.8Hz),2.95(2H, m), 3.07˜3.33(3H, m), 3.48(2H, m),     3.69(3H, s), 3.90(1H, ddd,7=7.4Hz×3), 4.06(1H, m), 4.75(1H, ddd,     J=5.6Hz), 6.36(1H, d, J=0.6Hz),6.57(1H, s), 6.58(1H, s), 7.11(1H, d,     J=1.8Hz), 7.28(6H, m), 7.49(1H, d, J=6.8Hz),8.69(1H, d, J=2Hz)  30     (N-morpho-lino)-methyl      ##STR168##      ##STR169##      NH      ##STR170##      48 0.58˜2.00(13H, m), 2.58(8H, m), 2.98(3H, m), 3.27 (4H, m),     3.60(1H, dd,J=4.8, 14.8Hz), 3.80(6H, m), 4.15(2H, m), 4.78(1H, m),     5.03(1H, d, J=4.5Hz),6.60(1H, d, J=9.4Hz), 7.18(1H, d, J=1.8Hz),     7.44(1H, s), 7.45(1H, ddd, J=7Hz×3),7.61(1H, t, J=7.2Hz), 7.72(1H,     t, J=7.0Hz), 7.86(1H, d, J=8.2Hz), 7.94(1H, d,J=7.0Hz, 8.42(1H , d,     J=8.2Hz), 8.86(1H, d, J=1.8Hz), 9.45(1H, d, J=7.8Hz)      31 (n-pyperi-dino)-methyl      ##STR171##      ##STR172##      NH      ##STR173##      58 0.60˜2.08(19H, m), 2.54(7H, m), 2.71(2H, m), 2.99(3H, m),     3.22(1H, m),3.28(2H, s), 3.60(2H, s), 3.60(1H, dd, J=5, 15Hz), 3.80(2H,     m), 4.14(2H, m), 4.80(1H, m),5.07(1H, bs), 6.64(1H, d, J=8.6Hz),     7.18(1H, d, J=1.8Hz), 7.45(2H, ddd,J=7.0Hz×3), 7.60(1H, t,     J=6.6Hz), 7.70(1H, t, J=6.6Hz), 7.86(1H, d, J=8.6Hz),7.94(1H, d, J=7.     8Hz, 8.24(1H, d, J=8.6Hz), 8.84(1H, d, J=1.8Hz), 9.34(1H, d,J=7.4Hz)  32     4-pyridyl      ##STR174##      ##STR175##      NH      ##STR176##      95 0.78˜1.68(13H, m), 2.45(2H, m), 2.75(3H, s), 2.83(3H, m),     3.10(3H, m),3.43(4H, m), 3.45(2H, m), 3.97(2H, m), 4.12(1H, m), 4.75(1H,     m), 5.16(1H, d,J=5Hz), 6.70(1H, d, J=9.4Hz), 6.92(1H, s), 7.33(5H, m),     7.82(2H, bs),8.85(2H, bs), 9.22(1H, d, J=7.6Hz)       33 phenyl     ##STR177##      ##STR178##      CH.sub.2      ##STR179##      71 0.70˜1.85(13H, m), 1.30(9H, s), 2.84(1H, m), 3.14(7H, m),     3.46(1H, m),4.06(1H, m), 4.13(1H, ddd, J=7Hz), 4.63(1H, m), 6.40(1H, d,     J=10Hz), 6.79(1H, s),7.25(5H, m), 7.48(2H, t, J=7.5Hz), 7.57(1H, m),     7.97(2H, m), 8.51(1H, m)      34 4-pyridyl CONH.sub.2     ##STR180##      NH      ##STR181##      70 0.79˜1.78(13H, m), 2.10(2H, m), 2.50(2H, m), 2.68(3H, m),     2.96(4H, m),3.13(2H, m), 3.93(1H, dd, J=3.6, 14.2Hz), 4.05(1H, m),     4.21(2H, m), 4.78(1H, m),7.28(1H, d, J=9.0Hz), 7.44(2H, d, J=4.4Hz),     7.58(2H, m), 7.88(4H, m), 8.20(1H, d,J=7.8Hz), 8.50(1H, d, J=8.0Hz),     8.80(2H, bs)      35 4-pyridyl SMe     ##STR182##      NH      ##STR183##      84 0.80˜1.80(13H, m), 2.14(3H, s), 2.63(2H, m), 2.96(1H, m),     3.26(3H, m),3.49(4H, m), 3.98(1H, dddd, J=5.0Hz×4), 4.12(1H, m),     4.25(1H, m), 4.65(1H, ddd,J=5.8Hz), 4.99(1H, d, J=5.4Hz), 6.90(1H, d,     J=10Hz), 7.30(5H, m), 7.78(2H, bs),8.83(2H, bs)      36 4-pyridyl     ##STR184##      ##STR185##      CH.sub.2      ##STR186##      89 0.78˜1.80(13H, m), 2.95˜3.55(10H, m), 3.99(1H, ddd,     J=7.8Hz), 4.18(1H,m),4.63(1H, ddd, J=5.6Hz), 6.39(1H, d, J=9.4Hz),     7.11(1H, d, J=1.8Hz), 7.38(2H, d,J=5.2Hz), 7.58(3H, m), 7.76(3H, m),     7.89(1H, m), 8.03(1H, d, J=7.8Hz),8.54(1H, d, J=1.8Hz), 8.80(2H, bs)  37     phenyl      ##STR187##      ##STR188##      CH.sub.2      ##STR189##      89 0.70˜1.82(13H, m), 1.22(3H, d, J=7Hz), 1.30(3H, d, J=7Hz),     1.90(1H, bs), 2.43(3H, s), 2.72˜3.23(8H, m), 3.49(1H, dd, J=13.2,     9.6Hz), 3.99(1H, m),4.19(1H, m), 4.57(1H, ddd, J=6Hz×3), 6.40(1H,     d, J=9.4Hz), 7.96(2H, d, J=6.8Hz),7.15˜7.32(6H, m), 7.34(2H, d,     J=8.4Hz), 7.42˜7.63(3H, m), 7.85(2H, d, J=8.4Hz),7.85(1H, d,     J=8.4Hz)      38 phenyl     ##STR190##      ##STR191##      CH.sub.2      ##STR192##      98 0.70˜1.83(13H, m), 1.23(3H, t, J=7.4Hz), 2.43(3H, s), 2.20(2H,     bs), 2.65˜3.24(8H, m), 3.50(1H, dd, J=9.6, 14.2Hz), 4.00(1H, m),     4.19(1H, m), 4.57(1H, ddd,7.80(2H, d, J=8.4Hz), 7.88(1H, s), 7.97(2H, d,     J=1.8Hz)      39 phenyl     ##STR193##      ##STR194##      CH.sub.2      ##STR195##      76 0.70˜1.80(13H, m), 2.28(1H, dd, J=6.2, 16.4Hz), 2.66(1H, dd,     J=4, 16.8Hz),2.92(3H, m), 3.05˜3.75(12H, m), 4.06(1H, m), 4.19(1H,     m), 4.79(1H, ddd, J=6.2Hz),6.78(1H, d, J=10Hz), 7.18(1H, d, J=1.8Hz),     7.30˜7.57(7H, m), 7.77(1H, d,J=7.8Hz), 7.88(1H, m), 8.04(3H, m),     8.29(1H, d, J=6.4Hz), 8.69(1H, d, J=1.8Hz)      40 phenyl     ##STR196##      ##STR197##      CH.sub.2      ##STR198##      81 0.80˜1.80(13H, m), 2.40(3H, s), 2.90˜3.75(17H, m),     4.06(1H, m), 4.22(1H, d,J=9.2Hz), 4.63(1H, ddd, J=5Hz), 6.87(1H, d,     J=9.6Hz), 7.18˜7.59(9H, m),7.74˜8.14(10H, m)  41 4-pyridyl      ##STR199##      ##STR200##      CH.sub.2      ##STR201##      76 0.70˜1.79(13H, m), 2.25(1H, dd, J=6.6, 17Hz), 2.74(1H, dd,     J=3.8, 16.8Hz),2.88(1H, dd, J=3.6, 16Hz), 2.96(3H, m), 3.08˜3.64(10     H, m)3.75(1H, dd,J=4.8, 13Hz), 4.12(2H, m), 4.75(1H, ddd, J=5.8Hz×3     ), 6.82(1H, d, J=9.4Hz),7.19(1H, d, J=2Hz), 8.77)2H, bs), 7.28(1H, d,     J=7.6Hz), 7.41(1H, t, J=7Hz),7.54(2H, ), 7.78(1H, d, J=8Hz), 7.87(3H, m)     , 8.03(1H, m), 8.46(1H, d, J=6.2Hz),8.71(1H, d, J=2Hz)  42 4-pyridyl      ##STR202##      ##STR203##      CH.sub.2      ##STR204##      79      43 4-pyridyl     ##STR205##      ##STR206##      NH      ##STR207##      95 0.70˜1.90(13H, m), 2.49(2H, m), 2.87(3H, m), 3.15(3H, m),     3.41(4H, m),3.57(2H, m), 3.97(2H, m), 4.11(1H, m), 4.74(1H, m), 5.11(1H,     d, J=5Hz), 6.59(1H, d,J=9.2Hz), 7.15(1H, d, J=2Hz), 7.32(5H, m),     7.85(2H, m), 8.85(1H, d, J=2Hz),8.85(2H, m), 9.34(1H, d, J=7Hz)  44     4-pyridyl      ##STR208##      ##STR209##      NH      ##STR210##      96 0.76˜1.86(13H, m), 1.95(2H, m), 2.50(2H, m), 2.66(2H, m),     2.88˜3.29(6H, m),3.58(1H, dd, J=5, 15Hz), 3.98(1H, m), 4.13(3H,     m), 4.79(1H, m), 5.05(1H, d,J=4.5Hz), 6.63(1H, d, J=10Hz), 7.17(1H, d,     J=1.7Hz), 7.43(2H, m), 7.59(2H, m0,7.88(4H, m), 8.69(1H, m), 8.8(1H, d,     J=2Hz), 8.55(2H, bs), 9.51(1H, d, J=7Hz)      45 cyclohexyl     ##STR211##      ##STR212##      NH      ##STR213##      94 0.77˜1.85(23H, m), 2.36(1H, m), 2.56(4H, m), 2.85(3H, m),     3.18(1H, dd,J=5.2, 14.4Hz), 3.49(6H, m), 3.90(3H, m), 4.75(1H, m),     5.01(1H, d, J=5.8Hz),6.55(1H, d, J=9.2Hz), 7.16(1H, d, J=1.8Hz),     7.32(5H, m), 8.84(1H, d, J=1.8Hz),9.10(1H, d, J=7.2Hz)  46 4-pyridyl      ##STR214##      ##STR215##      NH      ##STR216##      89 0.77˜1.80(13H, m), 2.35(6H, s), 2.75(1H, dd, J=10.6, 13.8Hz),     3.15(3H, m),3.43(1H, dd, J=3.8, 13.8Hz), 3.55(1H, dd, J=4.2, 15Hz),     3.75(1H, m), 3.95(2H, m),4.12(1H, m), 4.73(1H, m), 4.98(1H, d, J=5Hz),     6.63(1H, d, J=9.4Hz), 7.13(1H, d,J=2Hz), 7.31(5H, m), 7.85(2H, bs),     8.84(1H, d, J=2), 8.84(2H, bs), 9.39(1H, d,J=7.2Hz)  47 4-pyridyl      ##STR217##      ##STR218##      NH      ##STR219##      90 0.79˜1.80(13H, m), 2.30(2H, m), 2.42(2H, m), 2.85˜3.62(11     H, m), 3.94(1H, m),4.00(1H, m), 4.20(1H, m), 4.42(1H, m), 4.75(1H, m),     6.63(1H, d, J=9.4Hz),7.16(1H, d, J=2Hz), 7.29(5H, m), 7.71(1H, d,     J=4.4Hz), 7.85(2H, m), 8.33(1H, d,J=7Hz), 8.62(1H, d, J=2Hz), 8.83(2H,     bs)      48 4-pyridyl     ##STR220##      ##STR221##      NH      ##STR222##      94 0.79˜1.76(13H, m), 2.20(2H, m), 2.49(2H, m), 2.80˜3.08(4H     , m), 3.19˜3.56(7H, m),3.92(1H, dd, J=4.4, 14.2Hz), 4.00(1H, m),     4.20(1H, m), 4.55(1H, m), 4.74(1H, m),6.65(1H, d, J=9.6Hz), 7.15(1H, d,     J=1.6Hz), 7.45(2H, d, J=5.4Hz), 7.57(2H, m),7.85(4H, m), 8.19(1H, m),     8.33(1H, d, J=7), 8.52(1H, d, J=2Hz), 8.83(2H, bs)      49 m-2-(n-morpholi-no)ethoxy-phenyl      ##STR223##      ##STR224##      NH      ##STR225##      77 0.82˜1.80(13H, m), 2.19(2H, m), 2.33(2H, m), 2.60(4H, m),     2.77˜3.25(6H, m),d3.43(7H, m), 3.74(4H, m)3.83(1H, dd, J=5, 15Hz),     3.98(1H, m), 4.21(3H, m),4.63(1H, m), 4.76(1H, dddd, J=5.2Hz×4),     4.76(1H, m), 6.64(1H, d, J=9.8Hz), 7.12(1H, d, J=1.4Hz), 7.15(1H, m),     7.41(3H, m), 7.55(3H, m), 7.67(2H, m),7.84(2H, m), 8.17(1 H, m),     7.84(2H, m), 8.17(1H, m), 8.54(1H, d, J=2Hz)      50 4-pyridyl     ##STR226##      ##STR227##      NH      ##STR228##      83 0.60˜1.80(13H, m), 3.08(5H, m), 3.33(4H, m), 3.57(2H, m),     3.64(4H, m),4.05(1H, m), 4.18(1H, m), 4.65(1H, m), 4.95(1H, bs),     6.87(1H, d, J=9.8Hz),7.17(1H, d, J=1.2Hz), 7.30(5H, m), 8.17(2H, m),     8.58(1H, d, J=9Hz), 8.70(1H, d,J=1.2Hz), 8.84(2H, m)                     n      51 m-2-(N-morpholi-o)ethoxy-phenyl      ##STR229##      ##STR230##      CH.sub.2      ##STR231##      70 0.70˜1.80(13H, m), 2.28(1H, dd, J=6.6, 17.5Hz), 2.56(4H, m),     2.68(1H, dd,J=4, 16.6Hz), 2.80(3H, m), 2.95(1H, m), 3.18(2H, m),     3.35(4H, m), 3.50(2H, m),3.63(1H, dd, J=5.4, 12Hz), 3.71(4H, t, J=4.4Hz),      3.87(1H, d, J=7.4Hz),4.05(1H, m), 4.16(3H, t, J=5.6Hz), 4.77(1H, ddd,     J=6.4Hz×3), 6.79(1H, d,J=9.6Hz), 7.09(1H, dd, J=2.4, 8Hz),     7.18(1H, d, J=1.8Hz), 7.35(3H, m),7.54(3H, m), 7.63(1H, d, J=7.8Hz),     7.77(1H, d, J=7.6Hz), 7.88(1H, m), 8.02(1H, m),8.28(1H, d, J=6.4Hz),     8.70(1H, d, J=1.8Hz)      52 cyclohexyl     ##STR232##      ##STR233##      NH      ##STR234##      94 0.78(23H, m), 2.22(2H, m), 2.38(2H, m), 2.58(2H, m), 3.00(3H, m),     3.48(6H, m),3.82(1H, dd, J=5, 14.6Hz), 3.82(1H, m), 3.98(1H, m),     4.63(1H, m), 4.74(1H, ddd,J=8.8Hz), 6.56(1H, d, J=8.8Hz), 7.12(1H, d,     J=1.8Hz), 7.44(2H, m), 7.58(2H, dt,J=1.8, 6.4Hz), 7.80(1H, m), 7.89(1H,     m), 8.11(1H, d, J=7.8Hz), 8.22(1H, d,J=7.2Hz), 8.54(1H, d, J=1.8Hz)       Compd. [a].sub.D °     of C=1.0, CHCl.sub.3 Molecular formula     Ex. No. (Temp. °C.) (Molecular weight) Calcd. Found IR ν.sub.ma     x.sup.CHCl.sbsp.3 cm.sup.-1       23 -20.1 C.sub.37 H.sub.49 N.sub.3 O.sub.6 S.sub.2. C: 63.04 H:  7.15     C: 63.28 H:  7.21 3520, 3420, 3360(br)  (24) 1/2H.sub.2 O N:  5.96 S:     9.10 N:  5.91 S:  8.97 1670, 1600, 1580, 1450,   (704.94)     1118 24     -22.6 C.sub.36 H.sub.48 N.sub.4 O.sub.6 S.sub.2. C: 61.65 H:  6.77 C:     61.47 H:  7.02 3410, 3360, 1665, 1605,  (24) 1/4H.sub.2 O N:  7.99 S:     9.14 N:  8.01 S:  8.91 1595, 1505, 1450, 1410,   (708.93)      1115 25     -23.1 C.sub.35 H.sub.47 N.sub.3 O.sub.6 S.sub.3 C: 59.89 H:  6.75 C:     59.68 H:  6.71 3315, 1665, 1510, 1412,  (25) (701.948) N:  5.99 S: 13.70     N:  5.89 S: 13.41 1290, 1115 26 -19.6 C.sub.37 H.sub.55 N.sub.3 O.sub.6     S.sub.2. C: 62.51 H:  7.94 C: 62.60 H:  8.05 3520, 3420, 3360,  (24)     1/2H.sub.2 O N:  5.91 S: 9.02 N:  5.76 S:  8.87 (br-sh), 1665, 1605,     (710.99)      1510, 1450, 1118 27 -14.4 C.sub.43 H.sub.60 N.sub.4     O.sub.8 S.sub.2. C: 61.92 H:  7.37 C: 61.77 H:  7.51 3500, 3420, 3360,     1665,  (23.5) 1/2H.sub.2 O N:  6.72 S:  7.69 N:  6.52 S:  7.41 1596,     1581, 1505, 1460,   (834.101)     1448 28 (24.0) C.sub.38 H.sub.50     N.sub.6 O.sub.8 S.sub.2. C: 55.23 H:  6.30 C: 55.02 H:  6.07 3370, 1672,     1603, 1586,  -23.2 2/3H.sub.2 O.1/2CH.sub.2 Cl.sub.2 N: 10.04 S:  7.66     N: 10.01 S:  7.44 1511, 1450, 1406, 1341,  (MeOH) (836.462)     1262,     1158, 1116 29 -24.1 C.sub.36 N.sub.50 N.sub.4 O.sub.6 S.sub.2. C: 61.41     H:  7.49 C: 61.28 H:  7.43 3500, 3420, 3360, 1660,  (24.0) 1/2H.sub.2     O.1/4iPr.sub.2 O N:  7.64 S:  8.74 N:  7.50 S:  8.50 1605, 1530, 1508,     1462,   (733.490)     1450 30  C.sub.39 H.sub.54 N.sub.6 O.sub.8     S.sub.2. C: 57.88 H:  7.54 C: 57.65 H:  7.31 3380(3300), 1712, 1665,     3/2H.sub.2 O.3/4iPr.sub.2 O N:  9.31 S:  7.10 N:  9.59 S:      6.88 1600(1535), 1510,   (902.655)     1455, 1430 31  C.sub.40 H.sub.56     N.sub.6 O.sub.7 S.sub.2. C: 59.30 N:  7.37 C: 59.44 H:  7.45 3380(3280),     1705, 1662,   H.sub.2 O.1/4iPr.sub.2 O N: 10.00 S:  7.63 N:  9.88 S:     7.55 1600, 1535, 1510, 1450,   (840.587)     1400 32 -37.0 C.sub.36     H.sub.48 N.sub.6 O.sub.7 S.sub.2. C: 58.01 H:  6.56 C: 57.94 H:  6.53     3560, 3380(3300), 1675,  (24) 1/4H.sub.2 O N: 11.27 S:  8.60 N: 11.36 S:      8.36 1602, 1595, 1510(1535),  162-64   (745.044)     1455 34  C.sub.37     H.sub.48 N.sub.6 O.sub.8 S. C: 59.58 H:  6.62 C: 59.37 H:  6.66 3600,     3360, 1732, 1685,   1/2H.sub.2 O N: 11.27 S:  4.30 N: 11.39 S:  4.25     1664, 1640, 1600, 1545   (745.876) 35 -62.6 C.sub.23 H.sub.47 N.sub.5     O.sub.7 S.sub.2. C: 56.71 H:  6.92 C: 56.60 H:  6.77 3600, 3380,     1670(1690),  (24) 1/2H.sub.2 O N: 10.02 S:  9.17 N:  9.87 S:  9.01 1600,     (1515, 1525)  175-8  (698.886)     1500 36 -14.5(24) C.sub.43 H.sub.60     N.sub.4 O.sub.8 S.sub.2. C: 62.60 H:  7.33 C: 62.65 H:  7.13 3500, 3400,     3370, 1665,   3/2H.sub.2 O.1/2iPr.sub.2 O N:  6.79 S:  7.77 N:  6.79 S:     7.59 1598, 1510, (sh, 1550,   (825.074)     1525) 41 -19.7 C.sub.41     H.sub.49 N.sub.5 O.sub.6 S.H.sub.2 O C: 64.97 H:  6.78 C: 65.08 H:  6.82     3400, 3340, 1665, (sh,  (25.5) (757.947) N:  9.24 S:  4.23 N:  9.21 S:     3.95 1695), 1625, 1530, 1510,        1450, 1410 43 -33.2 C.sub.35     H.sub.46 N.sub.6 O.sub.7 S.sub.2 C: 57.83 H:  6.38 C: 57.89 H:  6.36     3560, 3540, 3380, (sh,  (25.5) (726.921) N: 11.56 S:  8.82 N: 11.47 S:     8.72 3300), 1665, 1500, 1530,        1510 44 -40.7(24) C.sub.41 H.sub.53     N.sub.2 O.sub.85 S.sub.2 C: 59.33 H:  6.44 C: 59.40 H:  6.50 3560, 3520,     3390, (sh  108-110 (830.014) N: 10.13 S:  7.73 N: 10.04 S:  7.50 3300),     1670, 1600, 1535,        1510 45 -34.6 C.sub.36 H.sub.53 N.sub.5 O.sub.7     S. C: 58.80 H:  7.78 C: 58.55 H:  7.55 3540, 3380, 3300, 1670,  (24)     3/4H.sub.2 O.1/2iPr.sub.2 O N:  8.79 S:  8.05 N:  9.05 S:  7.77 1605,     1530, 1510, 1450,   (796.554)     1408 46 -32.0 C.sub.33 H.sub.44     N.sub.6 O.sub.6 S.sub.3. C: 56.83 H:  6.91 C: 66.85 H:  6.82 3550,     3380(3300), 1665,  (25) 1/2H.sub.2 O.1/2iPr.sub.2 O. N: 10.97 S:  8.37     N: 11.14 S:  8.01 1605, 1596, 1530, 1510,   1/4CHCl.sub.2     1455, 1450     47  C.sub.37 H.sub.48 N.sub.6 O.sub.6 S. C: 60.71 H:  7.03 C: 60.79 H:     7.05   3/2H.sub.2 O.1/10iPr.sub.2 O N: 11.46 S:  4.37 N: 11.56 S:  4.31      (733.120) 48 -23.0(25) C.sub.41 H.sub.50 N.sub.6 O.sub.6 S. C: 68.34 H:      6.81 C: 63.34 H:  6.92 3520, 3340, 1670, 1600,   5/4H.sub.2 O N: 10.81     S:  4.12 N: 10.64 S:  3.81 1510(1530)   (777.444) 49 -19.3(25) C.sub.48     H.sub.62 N.sub.6 O.sub.8 S. C: 63.34 H:  7.20 C: 63.49 H:  7.27 3520,     3340, 1670, 1598,   3/2H.sub.2 O N:  9.23 S:  3.52 N:  9.35 S:  3.36     1580, 1510, (sh 1530)   (910.114) 50 -24.8 C.sub.36 H.sub. 46 N.sub.6     O.sub.6 S.sub.2.   C: 61.35 H:  7.03 3430(3480)3320, 1670,  (24) H.sub.2     O.1/5.D.sub.2 O   N: 11.36 S:  4.16 1640, 1603, 1510   (729.31)  51     -15.6 C.sub.48 Hj.sub.61 N.sub.5 O.sub.8 S. C: 65.39 H:  7.15 C: 65.63     H:  7.44 3400, 3340, 1668, (1635),  (25) 3/4H.sub.2 O N:  7.94 S:  3.64     N:  7.85 S:  3.39 1600, 1585, 1511,   (881.586)     1460, 1440 52 -26.0     C.sub.42 H.sub.57 N.sub.5 O.sub.6 S. C: 65.60 H:  7.60 C: 65.66 H:  7.68     3480, 3340, 1670, 1598,  (24) 1/2H.sub.2 O N:  9.11 S:  4.17 N:  9.08 S:      3.89 1508, (1525), 1448, 1425,   (768.990)     1410

    TABLE 10      ##STR235##      (IA)  Compd.    [α].sub.D °    of   Yield (C= 1.0, MeOH)     Elemental analysis Ex. No. R.sup.1 R.sup.4' % (°C.) Molecular     formula Calcd. Found IR νmax cm.sup.-1        2 phenyl tert- 75 .sup. -22.2° C.sub.37 H.sub.50 N.sub.4     O.sub.6 S. C: 64.82 C: 64.87 3460, 3360(br), 1663, 1600, 1580,   butyl     (24° C.) 1/2H.sub.2 O, 1/4iPr.sub.2 O H: 7.70 H: 7.65 1498, 1450,     1116       N: 7.85 N: 7.99       S: 4.49 S: 4.33  3 o-fluorophenyl tert-     90 -20.9 C.sub.37 H.sub.49 FN.sub.4 O.sub.6 S. C: 62.56 F: 2.67 C: 62.65     F: 2.71 3460, 3360(br), 1666, 1611, 1575,   butyl  (24.0) 3/4H.sub.2 O     H: 7.17 H: 7.12 1480, 1453, 1116       N: 7.89 N: 8.05       S: 4.51 S:     4.56  4 m-methoxyphenyl tert- 73 -18.1 C.sub.38 H.sub.52 N.sub.4 O.sub.7     S. C: 62.02 C: 62.05 3468, 3348(br), 1668, 1600, 1585,   butyl  (24.5)     1.5H.sub.2 O H: 7.53 H: 7.16 1499, 1464, 1451, 1430, 1289, 1258,     N: 7.61 N: 7.52 1169, 1117, 1077,       S: 4.36 S: 4.12      5 p-methylphenyl tert- 95 -21.3 C.sub.38 H.sub.52 N.sub.4 O.sub.6 S. C:     64.61 C: 64.65 3460, 3350(br), 1666, 1608, 1564,   butyl  (24.0)     3/4H.sub.2 O H: 7.63 H: 7.64 1498, 1450, 1116       N: 7.93 N: 7.99      S: 4.54 S: 4.61  6 2,4-difluoro- tert- 93 -21.0 C.sub.37 H.sub.48     F.sub.2 N.sub.4 O.sub.6 S. C: 61.39 F: 5.25 C: 61.18 F: 5.35 3470,     3350(br), 1665, 1612(1595sh),  phenyl butyl  (23.5) 1/2H.sub.2 O H: 6.82     H: 6.82 1498, 1450, 1430, 1116, 1100, 970,       N: 7.74 N: 7.76 855       S: 4.43 S: 4.40      ##STR236##      (IA)  Compd.    [α].sub.D °    of   Yield (C= 1.0, MeOH)     Elemental analysis Ex. No. R.sup.1 R.sup.4'  % (°C.) Molecular     formula Calcd. Found IR νmax cm.sup.-1        7 1-naphthyl tert- 60 -15.3 C.sub.41 H.sub.52 N.sub.4 O.sub.6 S. C:     65.53 C: 65.43 3672, 3352(br), 1665, 1605, 1509   butyl  (24.0) 5/4H.sub.     2 O H: 7.31 H: 7.09 1464, 1450, 1441, 1369, 1291, 1117,       N: 7.46 N:     7.37 1077       S: 4.27 S: 4.24  8 3-thienyl tert- 94 -24.4 C.sub.35     H.sub.45 N.sub.4 O.sub.6 S.sub.2. C: 59.81 C: 59.68 3460, 3350(br),     1662, 1600, 1505   butyl  (28.0) H.sub.2 O H: 7.17 H: 7.02 1446, 1113        N: 7.97 N: 8.23       S: 9.12 S: 9.10  9 2-thiazolyl tert- 71     C.sub.34 H.sub.47 N.sub.5 O.sub.6 S.sub.2. C: 56.45 C: 56.41 3660,     3356(br), 1661, 1599, 1511,   butyl   2H.sub.2 O.1/2C.sub.4 H.sub.8     O.sub.2 H: 7.24 H: 6.95 1446, 1113       N: 9.16 N: 9.14       S: 8.37     S: 8.09      ##STR237##      (IA)  Compd.   [α].sub.D °     of  Yield (C= 1.0, MeOH)     Ex. No. R.sup.1 % (°C.) Molecular formula Calcd. Found IR νmax     cm.sup.-1       10 m-fluorophenyl 88 -21.4 C.sub.37 H.sub.49 N.sub.4 FO.sub.6 S. C:     62.56 F: 2.67 C: 62.72 F: 2.60 3470, 3340, 1663, 1605, 1590,    (24.0)     3/4H.sub.2 O H: 7.17 H: 7.14 1496, 1445, 1400, 1370, 1115,      N: 7.89     N: 7.67 1075, 1015      S: 4.51 S: 4.60 11 p-fluorophenyl 87 -21.3     C.sub.37 H.sub.49 N.sub.4 FO.sub.6 S. C: 62.56 F: 2.67 C: 62.60 F: 2.66     3470, 3340, 1665, 1600, 1505,    (24.0) 3/4H.sub.2 O H: 7.17 H: 7.17     1450, 1410, 1370, 1156, 1115,      N: 7.89 N: 7.84 1076      S: 4.51 S:     4.62 12 2,6-difluoro- 75 -23.4 C.sub.37 H.sub.48 N.sub.4 F.sub.2 O.sub.6     S. C: 61.15 F: 5.23 C: 61.05 F: 5.26 3468, 3360, 1664, 1624, 1502,     phenyl  (23.5) 2/3H.sub.2 O H: 6.84 H: 6.60 1467, 1450, 1402, 1370,     1290,      N: 7.71 N: 7.77 1117, 1078, 1016, 991      S: 4.41 S: 4.75 13     o-methoxyphenyl 75  -3.3 C.sub.38 H.sub.52 N.sub.4 O.sub.7 S. C: 63.18     C: 63.18 3468, 3348, 1665, 1600, 1502,    (24.0) 3/4H.sub.2 O H: 7.46 H:     7.52 1487, 1465, 1438, 1280, 1163,      N: 7.76 N: 7.38 1117, 1077, 1026          S: 4.44 S: 4.03 14 o-chlorophenyl 75  -8.4 C.sub.37 H.sub.49     ClN.sub.4 O.sub.6 S. C: 61.23 Cl: 5.85 C: 61.03 Cl: 5.63 3468, 3360,     1665, 1593, 1500,    (23.5) 0.1 CH.sub.2 Cl.sub.2.1/3H.sub.2 O H: 6.91     H: 6.85 1450, 1435, 1402, 1370, 1291,      N: 7.70 N: 7.68 1117, 1077       S: 4.41 S: 4.31 15 m-cyanophenyl 92 -20.6 C.sub.38 H.sub.49 N.sub.5     O.sub.6 S. C: 61.82 C: 61.87 3468, 3360, 2236, 1666, 1602,    (24.5)     H.sub.2 O.1/4CHd.sub.2 Cl.sub.2 H: 6.99 H: 6.75 1499, 1450, 1431, 1401,     1370,      N: 9.42 N: 9.40 1288, 1150, 1117, 1077, 909      S: 4.31 S:     4.25 16 o-methylsulfonyl- 86 -11.4 C.sub.38 H.sub.53 N.sub.5 O.sub.8     S.sub.2. C: 58.82 C: 58.54 3464, 3352, 1664, 1607, 1578,  aminophenyl     (24.0) 1/4(iPr).sub.2 O.1/2H.sub.2 O H: 7.19 H: 7.06 1492, 1452, 1400,     1340, 1289,      N: 8.68 N: 8.46 1155, 1117, 1077, 968, 917      S: 7.95     S: 7.71 17 p-trifluorometyl- 95 -18.8 C.sub.38 H.sub.49 F.sub.3 N.sub.4     O.sub.6 S. C: 60.38 F: 7.54 C: 60.27 F: 7.53 3450, 3350, 1665, 1605,     1510,  phenyl  (24.0) 1/2H.sub.2 O H: 6.67 H: 6.77 1450, 1410, 1325,     1170, 1135,      N: 6.67 N: 7.27 1115, 1065       S: 4.24 S: 4.41      ##STR238##      (IA)  Compd.    [α].sub.D °     of   Yield (C= 1.0, MeOH)     Ex. No. R.sup.1 R.sup.4' % (°C.) Molecular formula Calcd. Found     IR νmax cm.sup.-1       18 m-morpholino- tert- 92 -15.8 ± 0.6 C.sub.42 H.sub.57 N.sub.5     O.sub.9 S. C: 60.09 C: 59.93 3470, 3320, 1711, 1680,  carbonyloxyphenyl     butyl  (25° C.) 13/4H.sub.2 O H: 7.26 H: 6.94 1665, 1605, 1587,     1500,       N: 8.34 N: 8.38 1420, 1370, 1116, 1068,       S: 3.82 S:     3.79 19 m-morpholino- tert- 79 -15.8 ± 0.6 C.sub.42 H.sub.57 N.sub.5     O.sub.8 S. C: 61.93 C: 61.70 3356, 1665, 1627, 1581,  carbonyloxyphenyl     butyl  (25° C.) 5/4 H.sub.2 O H: 7.36 H: 7.10 1498, 1463, 1451,     1369,       N: 8.60 N: 8.42 1289, 1117, 1075, 1028       S: 3.94 S: 3.92     20 3,4-methylene- tert- 88 -16.8 ± 0.6 C.sub.38 H.sub.50 N.sub.4     O.sub.8 S. C: 59.89 C: 59.86 3470, 3340, 1665, 1605,  dioxyphenyl butyl     (25° C.) 2H.sub.2 O.2/5 dioxane H: 7.26 H: 6.92 1505, 1490, 1445,     1117,       N: 7.05 N: 6.77 1080, 1042       S: 4.04 S: 3.87 21 cyclohexy     l tert- 94 -21.2 ± 0.6 C.sub.37 H.sub.56 N.sub.4 O.sub.6 S. C: 62.42     C: 62.42 3460, 3340, 1662(sh1685),   butyl  (24° C.) 1/2H.sub.2 O     H: 8.35 H: 8.06 1605, 1500, 1450, 1115       N: 7.87 N: 8.10       S:     4.50 S: 4.33 22 p-methoxyphenyl tert- 91 -16.9 ± 0.6 C.sub.38     H.sub.52 N.sub.4 O.sub.7 S. C: 60.21 C: 60.24 3470, 3340, 1665, 1603,     butyl  (24° C.) 2.5H.sub.2 O.1/2dioxan H: 7.71 H: 7.38 1575,     1510, 1170, 1116,       N: 7.02 N: 6.78 1076, 1030       S: 4.02 S: 3.77     37 phenyl isopropyl 93 -21.2 ± 0.6 C.sub.36 H.sub.48 N.sub.4 O.sub.6     S. C: 63.32 C: 63.59 3460, 3340, 1665, 1600,     (24° C.) H.sub.2     O H: 7.38 H: 7.46 1580, 1500, 1450, 1120,       N: 8.20 N: 8.01       S:     4.69 S: 4.48 38 phenyl ethyl 89 -22.1 ± 0.6 C.sub.35 H.sub.46 N.sub.4     O.sub.6 S. C: 63.28 C: 63.17 3400, 3350, 1665, 1600,     (24° C.)     3/4H.sub.2 O H: 7.21 H: 7.18 1582, 1510, 1450, 1310,       N: 8.43 N:     8.49 1123       S: 4.84 S: 4.60      ##STR239##      [IA]  Compd.      [α].sub.D °     of     Yield (C= 1.0,     MeOH) Ex. No. R.sup.1 R.sup.2 R.sup.4' X % (Temp. °C.) Molecular     formula Calcd. Found IR νmax cm.sup.-1       28 m-(N-methyl)- aminophenyl      ##STR240##      N-morpho-lino-sulfonyl NH 52 -25.5(25) C.sub.37 H.sub.50 N.sub.6     O.sub.7 S.sub.2.2/3H.sub.2 O.2/5CH.sub.2 Cl.sub.2 C: 56.09H: 6.56N:      S     10.49: 8.01 C: 56.16H: 6.56N: 10.24S: 7.64 3380, 1667, 1604, 1584,     1508,1454, 1448, 1410, 1339, 1294,1261, 1156, 1113, 1071 33 phenyl      ##STR241##      ter-butyl-sulfonyl CH.sub.2 44 -24.9  (23.5) C.sub.38 H.sub.50 N.sub.4     O.sub.6 S.sub.2.1/4H.sub.2 O(157.159° C: 62.11H: 7.12N: 7.83S:     8.96 C: 62.10H: 7.24N: 7.95S: 8.70 3490, 3400, 1665, 1605, 1580,1510,     1450, 1115      40 phenyl     ##STR242##      N-morpho-lino-carbonyl CH.sub.2 79 -15.8(25) C.sub.42 H.sub.51 N.sub.5     O.sub.6.2H.sub.2 O.2/5CH.sub.2 Cl.sub.2 C: 64.31H: 7.10N: 8.84 C:     64.38H: 6.82N: 8.97 3460, 3400, 3310, 1662, 1630,1600, 1580, 1510, 1490,     1450,1115, 1070      42 4-pyridyl     ##STR243##      N-morpho-lino-carbonyl CH.sub.2 79 -19.3(25) C.sub.41 H.sub.50 N.sub.6     O.sub.6.H.sub.2 O.1/2; Pr.sub.2 O C: 66.73H: 7.51N: 10.61 C: 66.54H:     N     7.54: 10.66 3460, 3400, 3320, 1660(sh1690),1625, 1520, 1490, 1460,     1445,1410, 1115       Compd.    of Ex. No.   NMR(δ ):        2   0.70˜1.83(13H, m), 1.33(9H, s), 2.68˜3.18(7H, m),     3.27(1H, m), 3.60(1H, dd, J=9.8, 13.2Hz),    3.80(1H, br), 3.99(1H, m),     4.21(1H, m), 4.60(1H, m), 6.48(1H, d, J=9.4Hz), 6.89(1H, s),    7.08.abou     t.7.63(8H, m), 7.50(1H, d, J=1.8Hz), 7.93(2H, d, J=8.4Hz)      3   0.68˜1.83(13H, m), 1.33(9H, s), 2.70˜3.17(7H, m),     3.60(1H, dd, J=13.1, 9.9Hz), 3.59(2H, brs),    3.25(1H, m), 3.98(1H, m),     4.18(1H, m), 4.59(1H, ddd, J=6.8, 6.8, 6.8Hz), 6.51(1H, d, J=9.0Hz),     6.90(1H, s),    7.05˜7.37(7H, m), 7.52(1H, m), 7.56(1H, s),     7.84(1H, ddd, J=7.7, 1.9Hz)  4   0.70˜1.83(13H, m), 1.32(9H, s),     2.74˜3.17(7H, m), 3.27(1H, m), 3.59(1H, dd, J=10.13, 13Hz),     3.83(3H, s), 4.00(1H, m), 4.20(1H, m), 4.60(1H, ddd, J=7, 7, 7Hz),     4.72(1H, bs), 6.60(1H, d, J=9Hz),    6.86(1H, s), 7.04˜7.55(9H,     m), 7.48(1H, s)  5   0.70˜1.85(13H, m), 1.32(9H, s), 2.40(3H, s),     2.70˜3.18(7H, m), 3.27(1H, m),    3.61(1H, dd, J=13.2, 9.8Hz),     3.75(2H, bs), 3.99(1H, m), 4.19(1H, m), 4.61(1H, ddd, J=6.5, 6.5,     6.5Hz),    6.53(1H, d, J=9Hz), 6.88(1H, s), 7.10˜7.45(7H, m),     7.52(1H, s), 7.82(2H, d, J=8.2Hz)  6   0.70˜1.80(13H, m), 1.34(9H,     s), 2.77˜3.16(7H, m), 3.20(2H, bs), 3.25(1H, m),    3.59(1H, dd,     J=13.95Hz), 3.48(1H, m), 4.18(1H, m), 4.59(1H, ddd, J=7, 7, 7Hz),     6.46(1H, d, J=9.3Hz),    6.78˜7.00(2H, m), 6.91(1H, s), 7.23(5H,     m), 7.54(1H, s), 7.91(1H, ddd, J=8.6, 8.6, 6.6Hz)      7   0.70˜1.85(13H, m), 1.30(9H, s), 2.82(1H, dd, J=13.2, 8.4Hz),     2.90˜3.18(6H, m), 3.28(1H, m),    3.59(1H, dd, J=13.0, 10.0Hz),     4.03(1H, m), 4.24(1H, m), 4.60(1H, ddd, J=5, Hz), 5.30(1H, brs),     6.63(1H, d, J=9.2Hz),    6.83(1H, s), 7.20(5H, m), 7.50(4H, m), 7.90(2H,     m), 7.86(1H, s), 8.60(1H, d, J=7.6Hz)  8   0.70˜1.85(13H, m),     1.33(9H, s), 2.77˜3.18(7H, m), 3.26(1H, m), 3.59(1H, dd, J=13.2,     10.2Hz),    3.97(1H, m), 4.18(1H, m), 4.58(1H, m), 6.44(1H, d, J=9.4Hz),     6.88(1H, s), 7.12˜7.47(6H, m),    7.50(1H, s), 7.51(1H, dd, J=5.0,     1.2Hz), 8.13(1H, dd, J=1.2, 3Hz)  9   0.70˜1.83(13H, m), 1.34(9H,     s), 2.74˜3.328H, m), 3.61(1H, dd, J=12.8, 9.4Hz), 3.73(2H, bs),     3.95(1H, m), 4.23(1H, m), 4.60(1H, ddd, J=6.6, 6.6, 6.6Hz), 6.51(1H, d,     J=9.2Hz), 6.96(1H, s), 7.12˜7.35(5H, m),    7.57(1H, s), 7.68(1H,     d, J=3Hz), 8.00(1H, d, J=3Hz)       Compd.    of   [IA] Ex. No. R.sup.3 X NMR(δ )       10   0.70˜1.82(13H, m), 1.33(9H, s), 2.75˜3.19(7H, m),     3.28(1H, m), 3.62(1H, dd, J=13, 10Hz), 4.02(1H, m),    4.20(1H, m),     4.59(1H, ddd, J=6.4, 6.4, 6.4Hz), 6.55(1H, d, J=9.4Hz), 6.92(1H, s),     7.25(6H, m),    7.45(2H, m), 7.56(1H, s), 7.62(1H, m), 7.70(1H, d,     J=7.6Hz) 11   0.70˜1.82(13H, m), 1.33(9H, s), 2.75˜3.20(7H,     m), 3.28(1H, m), 3.57(2H, bs), 3.60(1H, dd, J=13, 10Hz),    4.00(1H, m),     4.19(1H, m), 4.59(1H, ddd, J=6.6, 6.6, 6.6Hz), 6.54(1H, d, J=9.2Hz),     6.90(1H, s),    7.14(2H, dd, J=17.2, 8.8Hz), 7.26(6H, m), 7.48(1H, d,     J=8Hz), 7.54(1H, s), 7.96(2H, dd, J=9, 5.4Hz) 12   0.70˜1.85(13H,     m), 1.33(9H, s), 2.78˜3.18(7H, m), 3.25(1H, m), 3.61(1H, dd,     J=13.2, 9.8Hz),    3.95(1H, m), 4.12(1H, m), 4.58(1H, ddd, J=6.4, 6.4,     6.4Hz), 5.68(2H, bs), 6.55(1H, d, J=9.4Hz)    6.85(1H, s), 6.93(2H, t,     J=8.2Hz), 7.15˜7.48(7H, m), 7.49(1H, s) 13   0.70˜1.82(13H,     m), 1.33(9H, s), 2.75˜3.35(8H, m), 3.62(1H, dd, J=14, 10Hz),     3.87(3H, s), 3.95(1H, m),    4.15(1H, m), 4.62(1H, ddd, J=6.5, 6.5,     6.5Hz), 6.66(1H, d, J=9.4Hz), 6.82(1H, s), 6.85(2H, m), 7.24(5H, m),     7.46(1H, s), 7.46(1H, td, J=7.8, 1.8Hz), 7.70(1H, dd, J=7.8, 1.8Hz) 14     0.70˜1.80(13H, m), 1.33(9H, s), 2.78˜3.17(7H, m), 3.52(1H,     dd, J=13.9, 8Hz), 3.97(1H, m),    4.13(1H, m), 4.57(1H, ddd, J=6.7, 6.7,     6.7Hz), 6.52(1H, d, J=9.0Hz), 6.85(1H, s), 7.14˜7.42(8H, m),     7.46(1H, s), 7.53(1H, m), 15   0.70˜1.80(13H, m), 1.33(9H, s),     2.77˜3.18(7H, m), 3.29(1H, dd, J=12.8, 9.8Hz),    4.04(1H, m),     4.22(1H, m), 4.57(1H, ddd, J=5.8, 5.8, 5.8Hz), 6.59(1H, d, J=6.91(1H,     s),    7.23(5H, m), 7.56(1H, s), 7.58(1H, t, J=7.8Hz), 7.81(1H, d,     J=7.8Hz), 8.14(1H, d, J=8Hz), 8.23(1H, s) 16   0.70˜1.82(13H, m),     1.33(9H, s), 2.75˜3.17(7H, m), 3.26(1H, m), 3.59(1H, dd, J=13,     10.4Hz), 4.01(1H, m),    4.16(1H, m), 4.57(1H, ddd, J=6l4, 6.4, 6.4Hz),     6.59(1H, d, J=9.2Hz), 6.88(1H, s), 7.20(6H, m), 7.49(1H, d, J=1.2Hz),     7.50(2H, m), 7.69(1H, dd, J=8.4, 1.2Hz), 7.86(1H, dd, J=8.2, 1.2Hz) 17     0.70˜1.80(13H, m), 1.32(9H, s), 2.75˜3.18(7H, m), 3.27(1H,     m), 3.58(1H, dd, J=13.4, 4.10Hz), 4.04(1H, m),    4.21(1H, td, J=7,     2.5Hz), 4.57(1H, ddd, J=6.3, 6.3, 6.3Hz), 6.54(1H, d, J=9.4Hz), 7.25(5H,     m),    7.52(1H, d, J=9Hz), 7.71(2H, d, J=8.2Hz), 8.04(2H, d, J=8Hz) 18     0.70˜1.83(13H, m), 1.34(9H, s), 2.70˜3.15(7H, m), 3.28(1H,     m), 3.48˜3.82(8H, m), 3.88(1H, m),    4.14(1H, m), 4.63(1H, ddd,     J=6.6, 6.6, 6.6Hz), 6.39(1H, d, J=8.6Hz), 6.80(1H, s), 7.17˜7.40(6H     , m),    7.40˜7.60(3H, m), 7.77(1H, d, J=7.6Hz) 19   0.70˜1.8     0(13H, m), 1.33(9H, s), 2.63˜3.17(7H, m), 3.30(1H, m), 3.38˜3     .95(10H, m), 4.18(1H, m),    4.63(1H, ddd, J=6, 6, 6Hz), 6.49(1H, d,     J=8.8Hz), 6.86(1H, s), 7.23(6H, m), 7.56(1H, s), 7.55(1H, m),     7.71(1H, d, J=6Hz), 7.84(1H, s), 8.00(1H, m) 20   0.70˜1.82(13H,     m), 1.34(9H, s), 2.78˜3.18(7H, m), 3.26(1H, m), 3.60(1H, dd,     J=13.9, 8Hz), 3.97(1H, m),    4.17(1H, m), 4.60(1H, ddd, J=6.4, 6.4,     6.4Hz), 6.04(2H, s), 6.45(1H, d, J=9.4Hz), 6.84(2H, d, J=8.2Hz),     6.86(1H, s), 7.25(5H, m), 7.39(1H, d, J=1.2Hz), 7.49(1H, s), 7.51(2H, d,     J=8.2Hz) 21   0.70˜1.92(23H, m), 1.35(9H, s), 2.36(1H, m),     2.55(2H, m), 2.75˜3.18(5H, m), 3.26(1H, m),    3.60(1H, dd,     J=13.3, 9.8Hz), 3.88(1H, m), 3.99(1H, m), 4.56(1H, ddd, J=6, 6, 6Hz),     6.41(1H, d, J=9.2Hz),    6.88(1H, s), 7.27(5H, m), 7.54(1H, s) 22     0.70˜0.83(13H, m), 1.34(9H, s), 2.75˜3.17(7H, m), 3.15(1H,     m), 3.60(1H, dd, J=13, 9.6Hz), 3.87(3H, s),    3.98(1H, m), 4.18(1H, m),     4.61(1H, ddd, J=6.8, 6.8, 6.8Hz), 6.44(1H, d, J=9.2Hz), 6.86(1H, s),     6.93(2H, d, J=9Hz),    7.25(5H, m), 7.49(1H, s), 7.91(2H, d, J=8.6Hz) 23       0.70˜1.85(13H, m), 1.23(3H, d, J=6.8Hz), 1.30(3H, d, J=6.8Hz),     2.70˜3.18(8H, m), 3.22(1H, m),    3.56(1H, dd, J=13.4, 9.6Hz),     4.01(1H, m), 4.20(1H, m), 4.60(1H, ddd, J=6.6Hz), 6.49(1H, d, J=9.2Hz),       6.87(1H, s), 7.22(5H, m), 7.50(4H, m), 7.93(2H, d, J=6.8Hz) 38     0.70˜1.85(13H, m), 1.23(3H, t, J=7.4Hz), 2.65(8H, m), 3.23(1H, m),     3.57(1H, dd, J=14, 9.8Hz),    4.03(1H, m), 4.19(1H, m), 4.62(1H, ddd,     J=6.2, 6.2, 6.2Hz), 6.56(1H, d, J=9.2Hz), 6.88(1H, s),    7.20(5H, m),     7.45(1H, d, J=1.6Hz), 7.52(3H, m), 7.93(2H, d, J=6.8Hz)      28     ##STR244##      NH 0.65˜1.77(13H, m), 2.50(2H, m), 2.80(3H, m), 2.89(3H, s),     3.00(2H, m), 3.20(1H, dd, J=5.15Hz), 3.40(4H, m), 3.53(1H, dd, j=5,     15Hz), 3.95(2H, m), 4.12(1H, m), 4.80(1H, dt, J=r.r, 7.0Hz), 5.18(1H, d,     J=6Hz), 6.62(1H, d, J=9.4Hz), 6.82(1H, dt, J=2.2, 7Hz), 7.14(1H, d,     J=2Hz), 7.30(8H, m), 8.81(1H, d, J=2Hz), 9.09(1H, d, J=6.8Hz)  33      ##STR245##      CH.sub.2 0.70˜1.82(13H, m), 1.31(9H, s), 2.83˜2.20(9H, m),     3.47(1H, dd, J=4.6, 13.2Hz), 4.01(1H, m), 4.16(1H, dt, J=3, 6.2Hz),     4.60(1H, ddd, J=4.8Hz×3), 5.30(1H, bs), 6.24(1H, s), 6.49(1H, d,     J=9.8Hz), 7.25(5H, m), 7.47(2H, t, J=7.4Hz), 7.56(1H, d, J=7Hz),     7.62(1H, d, J=6.8Hz), 7.96(2H, dd, J=1.4, 6.6Hz)      40     ##STR246##      CH.sub.2 0.78˜1.80(13H, m), 2.56(2H, m), 2.90˜3.70(15H, m),     4.04(1H, m), 4.21(1H, m), 4.64(1H, ddd, J=6.2Hz), 6.68(1H, d, J=10Hz),     6.87(1H, s), 7.26˜7.59(8H, m), 7.76(1H, d, J=8.2Hz), 7.87(1H, m),     8.02(3H, m),      42     ##STR247##      CH.sub.2 0.67˜1.77(13H, m), 2.47(1H, dd, J=7.5, 17Hz), 2.62(1H,     dd, J=5, 18Hz), 2.88˜3.76(15H, m), 4.08(1H, m), 4.17(1H, m),     4.63(1H, ddd, J=5Hz), 6.77(1H, d, J=10Hz), 6.88(1H, s), 7.29(1H, d,     J=7.5Hz), 7.40(1H, t, J=7.5Hz), 7.54(3H, m), 7.80(2H, d, J=6.2Hz),     7.80(2H, m), 8.04(1H, m), 8.33(1H, m), 8.76(2H, d, J=6Hz)

EXAMPLES 53 ##STR248##

To the compound [25a] (24.5 g, 41.6 mmol) are added anisole (89.7 g, 20eq) and anhydrous dichloromethane (250 ml). To the mixture is dropwiseadded trifluoroacetic acid (250 ml) with stirring and ice-cooling over30 minutes, and the mixture is stirred at room temperature for one hour.The reaction mixture is concentrated in vacuo, made alkaline with Na₂CO₃ and saturated aqueous sodium bicarbonate, and extracted with amixture of dichloromethane and methanol (9:1). The organic layer iswashed with water, dried over MgSO₄, and evaporated to dryness in vacuo.The residue is subjected to silica gel chromatography (Si02 600 g, CH₂Cl₂ :MeOH:NH₄ OH=90:10:1) to obtain the compound [26a] (14.63 g, 72%).

To the above compound [26a] (11.04 g, 22.5 mmol) are addedN-(morpholinosulfonyl)phenylalanine [12a] (8.5 g, 1.2 eq), HOBt (3.96 g,1.25 eq), and anhydrous CH₃ CN (200 ml) To the mixture is added DCC(6.05 g, 1.3 eq) with stirring and ice-cooling, and the mixture isstirred at 0° C. for one hour and then at room temperature foradditional one hour. The reaction mixture is added with ethyl acetateand filtered. The filtrate is concentrated in vacuo and subjected tosilica gel chromatography (SiO₂ : 600 g, CH₂ Cl₂ :MeOH=97:3). Relevantfractions are combined and treated with isopropyl ether to give thecompound [Ib] (16.33 g, 92%)

Elemental analysis (as C₃₃ H₅₁ N₇ O₉ S₃.0.75H₂ O.1.0CH₂ Cl₂):

Calcd.: C: 49.20; H: 6.57; N: 12.13; S 11.90:

Found C: 49.05; H: 6.20; N: 11.92; S 11.78:

[α]_(D) =-22.5 (c=1; MeOH; 24° C.)

IR: 3370, 2720, 1665, 1530, 1510, 1454, 1340, 1330, 1260, 1155, 1113,1073, 943

NMR(δ): 0.72(3H,m), 1.12(6H,m), 4.16(1H,bd,J=8Hz), 1.62(3H,bd,J=8Hz),2.21(1H,bs), 2.47(2H,m), 2.74(1H,dd,J=10.14Hz), 2.80-3.33(4H,m),3.21(4H,m),3.33-3.62(8H,m), 3.75(4H,m), 3.97(2H,m), 4.68(1H,m),5.16(1H,d,J=5.4Hz), 5.64(1H,t,J=6.8Hz), 6.55(1H,d,J=9.2Hz),7.19(1H,d,J=1.2Hz), 7.35(5H,m), 8.90(1H,d,J=1.2Hz), 9.40(1H,d,J=6.8Hz)

EXAMPLES 54-71

In accordance with substantially the same procedure as disclosed inExample 53, the compounds of the invention listed in Table 11 areobtained.

    TABLE 11      ##STR249##        Compd.  [IB] of      Yield [α].sub.D.sup.0 C=1, Molecular     Elemental analysis  Ex. No. R.sup.1 R.sup.2 R.sup.3 X R.sup.4 % MeOH     (°C.) formula Calcd. Found IR νmax cm.sup.-1       54      ##STR250##      ##STR251##      ##STR252##      NH      ##STR253##      82 -38.4(24.0) C.sub.37 H.sub.53 N.sub.7 O.sub.9S.sub.3.0.75H.sub.2     O.0.33(ipr).sub.2 O C: 53.01H: 6.75N: 11.10S: 10.89 C: 52.38H: 6.48N:     10.96S: 10.75 3370, 2920, 1730, 1665,1600, 1530, 1510, 1400,1340, 1260,     1155, 1115,1072, 940      55     ##STR254##      ##STR255##      ##STR256##      NH      ##STR257##      83 -15.3(24)   C.sub.39 H.sub.55 N.sub.7 O.sub.8S.sub.3.0.66H.sub.2     O.0.25CH.sub.2 Cl.sub.2 C: 55.65H: 6.76N: 11.57S: 7.57 C: 55.62H: 6.54N:     11.41S: 7.18 3340, 2920, 1670, 1600,1530, 1510, 1505, 1335,1261, 1155,     1116, 1075      56 NMe.sub.2     ##STR258##      ##STR259##      NH      ##STR260##      98 -22.9(25.0) C.sub.31 H.sub.49 N.sub.7 O.sub.8S.sub.3.0.5H.sub.2     O.0.25CH.sub.2 Cl.sub.2 C: 48.48H: 6.58N: 12.66S: 12.42 C: 48.59H:     6.48N: 12.28S: 11.37 3370, 2920, 1665, 1604,1530, 1510, 1400, 1328,1260,     1153, 1113, 950      57 NMe.sub.2     ##STR261##      ##STR262##      NH      ##STR263##      89  -7.4(24.0) C.sub.32 H.sub.51 N.sub.5 O.sub.7S.sub.3.0.2H.sub.2     O.0.1(ipr).sub.2 O C: 53.80H: 7.31N: 9.62S: 13.22 C: 53.61H: 7.25N:     9.40S: 12.73 3360, 2920, 1665, 1530, 1510, 1448, 1325, 1290,1145, 1115,     955      58     ##STR264##      ##STR265##      ##STR266##      NH      ##STR267##      92 -23.7(25.0) C.sub.34 H.sub.47 N.sub.7 O.sub.8S.sub.3.0.5H.sub.2     O.0.25CH.sub.2 Cl.sub.2 C: 50.90H: 6.05N: 12.13S: 11.90 C: 50.96H:     5.98N: 12.10S: 11.68 3380, 2930, 1665, 1605,1577, 1530, 1512, 1415,1340,     1260, 1160, 1115,1075, 945      59     ##STR268##      ##STR269##      ##STR270##      NH      ##STR271##      86 -17.6(25.0) C.sub.40 H.sub.51 N.sub.7 O.sub.7S.sub.2.0.5H.sub.2     O.0.25CH.sub.2 Cl.sub.2 C: 57.81H: 6.33N: 11.72S: 7.67 C: 57.84H: 6.32N:     11.69S: 7.55 3330, 2920, 1670, 1599,1575, 1580, 1505, 1336,1165, 1115     60      ##STR272##      ##STR273##      ##STR274##      CH.sub.2      ##STR275##      70 -15.0(23.5) C.sub.39 H.sub.51 N.sub.5 O.sub.7S.sub.3.0.2H.sub.2 O C:     58.43H: 6.46N: 8.74S: 12.00 C: 58.20H: 6.27N: 8.59S: 11.75 3360, 2920,     1615, 1600,1567, 1530, 1500, 1450, 1330, 1290      61     ##STR276##      ##STR277##      ##STR278##      CH.sub.2      ##STR279##      83  -3.4(23.5) C.sub.34 H.sub.48 N.sub.4 O.sub.7S.sub.4.0.75H.sub.2 O     C: 53.28H: 6.51N: 7.31S: 16.73 C: 53.04H: 6.22N: 7.56S: 16.63 3360,     2920, 1660, 1530,1510, 1450, 1405, 1338, 1290, 1155, 1115, 1015  62      ##STR280##      ##STR281##      ##STR282##      CH.sub.2      ##STR283##      72  -3.8(25.5) C.sub.36 H.sub.50 N.sub.4 O.sub.7S.sub.3.0.5H.sub.2 O C:     57.19H: 6.80N: 7.41S: 12.72 C: 57.01H: 6.69N: 7.41S: 11.81 3360, 2920,     1660, 1605,1530, 1510, 1446, 1330, 1290, 1160, 1165, 1145,1116, 1115  63      ##STR284##      ##STR285##      ##STR286##      CH.sub.2      ##STR287##      88  -5.4(25.5) C.sub.37 H.sub.52 N.sub.4 O.sub.7S.sub.3 C: 58.39H:     6.89N: 7.36S: 12.64 C: 58.20H: 7.08N: 7.32S: 12.35 3340, 3360, 1662,     1605,1585, 1510, 1450, 1330,1290, 1160, 1115, 1095      64     ##STR288##      ##STR289##      ##STR290##      NH      ##STR291##      74 -23.5(25.5) C.sub.35 H.sub.55 N.sub.7 O.sub.9S.sub.3.0.75H.sub.2 O     C: 50.80H: 6.88N: 11.85S: 11.02 C: 50.98H: 6.86N: 11.90S: 11.46 3380,     2920, 1665, 1605,1530, 1510, 1405, 1327,1260, 1153, 1115, 1070  65      ##STR292##      ##STR293##      ##STR294##      NH      ##STR295##      74 -16.8(25.5) C.sub.41 H.sub.59 N.sub.7 O.sub.8S.sub.2.H.sub.2 O C:     57.64H: 7.15N: 11.40S: 7.45 C: 57.12H: 6.93N: 11.21S: 7.36 3330, 3000,     1670, 1597,1525(should), 1507,1330, 1143, 1124      66     ##STR296##      ##STR297##      ##STR298##      NH      ##STR299##      83 -19.9(25.0) C.sub.36 H.sub.57 N.sub.7 O.sub.9S.sub.3.H.sub.2     O.0.33CH.sub.2 Cl.sub.2 C: 49.92H: 6.88N: 11.22S: 11.00 C: 49.76H:     6.63N: 11.10S: 10.66 3380, 2930, 1665, 1605,1530, 1510, 1325, 1263,1155,     1116, 1075, 945      67     ##STR300##      ##STR301##      ##STR302##      NH      ##STR303##      86 -14.9(25.0) C.sub.42 H.sub.61 N.sub.7 O.sub.8S.sub.2.H.sub.2     O.0.5CH.sub.2 Cl.sub.2 C: 55.69H: 7.04N: 10.70S: 7.00 C: 55.48H: 6.86N:     10.82S: 6.66 3330, 2920, 1670, 1600,1530, 1505, 1446, 1330,1142, 1115     68      ##STR304##      ##STR305##      ##STR306##      NH      ##STR307##      80 -23.8(25.5) C.sub.33 H.sub.53 N.sub.7 O.sub.8S.sub.3.H.sub.2 O C:     50.17H: 7.02N: 12.41S: 12.17 C: 50.08H: 6.80N: 12.41 S: 11.99 3380,     2920, 1665, 1510,1328, 1262, 1155, 1115      69 CH.sub.3     ##STR308##      ##STR309##      CH.sub.2      ##STR310##      89 -11.1(24.0) C.sub.31 H.sub.48 N.sub.4 O.sub.7S.sub.3.0.5H.sub.2     O.0.33CH.sub.2 Cl.sub.2 C: 52.51H: 6.97N: 7.58S: 13.01 C: 52.25H: 6.80N:     7.80S: 12.51 3350, 2920, 1660, 1604, 1525, 1510, 1325, 128601146, 1114     70      ##STR311##      ##STR312##      ##STR313##      CH.sub.2      ##STR314##      90  -7.0(23.5) C.sub.34 H.sub.54 N.sub.4 O.sub.7S.sub.3.0.33H.sub.2 O.     C: 55.72H: 7.52N: 7.64S: 13.12 C: 55.58H: 7.39N: 7.57S: 12.38 3360,     2920, 1660, 1605,1530, 1510, 1450, 1325, 1290, 1140, 1115      71     ##STR315##      ##STR316##      ##STR317##      CH.sub.2      ##STR318##      70  -6.6(24.0) C.sub.39 H.sub.55 N.sub.5 O.sub.7S.sub.2.0.75H.sub.2 O     C: 59.78H: 7.27N: 8.94S: 8.18 C: 59.81H: 7.10N: 8.85S: 7.89 3340, 2930,     1665, 1628,1530, 1510, 1447, 1326,1142, 1126       Compd.  of Ex. No. [IB]NMRδ       54 0.74(3H, m), 1.12(6H, m), 1.42(1H, bd), 1.60(3H, bd, 7.5Hz),     1.95(2H, m), 2.05(1H, bs), 2.52(2H, m), 2.65(2H, m), 3.00(5H, m),     3.21(5H, m), 3.55(2H, m), 3.78(4H, m), 3.88(1H, m), 4.06˜4.25(2H,     m),  4.74(1H, m), 5.01(1H, d, J=4.Hz), 5.62(1H, t, J=7.5Hz), 6.56(1H, d,     J=9.2Hz), 7.18(1H, d, J=1.6Hz), 7.45(1H, m), 7.56˜7.76(2H, m),     7.87(1H, dd, J=1.4, 8.2Hz), 7.93(1H, dd, J=1, 7.8Hz), 8.23(1H, d,     J=8.4Hz), 8.89(1H, dJ=2Hz), 9.61(1H, d, J=6.8Hz) 55 0.76(3H, m),     0.95˜1.53(6H, m), 1.60(4H, bd), 1.80(1H, bs), 2.25(2H, m),     2.42(2H, m), 2.80(1H, m), 3.04(4H, m), 3.19(4H, m), 3.46(7H, m),     3.63(1H, m), 3.75(4H, m), 3.92(1H, dd, J=4.3, 14.3Hz),  3.93 (1H, m),     4.51(1H, m), 4.70(1H, m), 5.58(1H, bt), 6.81(1H, d, J=9.5Hz), 7.16(1H,     d, J=2.0Hz), 7.46(2H, m), 7.59(2H, m), 7.83(2H, m), 7.89(1H, m),     8.16(1H, d, J=8.2Hz), 8.35(1H, d, J=  7.0Hz), 8.61(1H, d, J=1.9Hz) 56     0.60˜2.00(13H, m), 2.48(2H, m), 2.58(1H, bs), 2.81(6H, s),     2.68˜3.12(4H, m), 3.16˜3.63(9H, m), 3.97(2H, m), 4.71(1H,     m), 5.27(1H, d, J=5.4Hz), 5.52(1H, bt), 6.57(1H, d, J=9.2Hz), 7.20(1H,     d, J=  1.8Hz), 7.37(5H, m), 8.90(1H, d, J=1.8Hz), 9.37(1H, d, J=6.8Hz)     57 0.70˜1.80(13H, m), 1.34(9H, s), 2.79(6H, s), 2.32˜3.53(9H,      m), 3.67(1H, m), 3.94(1H, m), 4.67(1H, ddd, J=6Hz×3), 5.73(1H,     bt), 6.59(1H, d, J=9.4Hz), 7.27(6H, m), 7.53(1H, d, J=6.6Hz), 8.86(1H,     d,  J=2) 58 0.75(3H, m), 1.13(5H, m), 1.43(1H, m), 1.60(4H, m), 2.52(4H,     m), 2.83(5H, m), 3.22(1H, dd, J=5, 15Hz), 3.44(6H, m), 3.87(1H, m),     4.03(1H, m), 4.65(1H, m), 5.33(1H, d, J=5.6Hz), 6.29(1H, t,  J=6.3Hz),     6.58(1H, d, J=9.0Hz), 7.16(1H, d, J=1.8Hz), 7.33(6H, m), 7.49(1H, m),     8.20(1H, d, J=8Hz), 8.79(1H, bd), 8.85(1H, d, J=2.0Hz), 9.11(1H, bs),     9.30(1H, d, J=7.0Hz) 59 0.73(3H, bs), 0.92˜1.48(6H, m), 1.60(4H,     bd), 2.26(2H, m), 2.40(2H, m), 2.73(1H, m), 3.00(4H, m), 3.44(8H, m),     3.85(1H, dd, J=4.2, 14.4Hz), 3.86(1H, m), 4.49(1H, m), 4.63(1H, m),     6.23(1H, bt), 6.80  (1H, d, J=9.2Hz), 7.15(1H, d, J=1.6Hz), 7.45(2H, m),     7.58(2H, m), 7.70˜7.96(3H, m), 8.16(2H, t, J=9Hz), 8.29(1H, d,     J=6.8Hz), 8.58(1H, d, J=1.8Hz), 8.77(1H, m), 9.11(1H, bs) 60 0.55˜1     .70(13H, m), 1.35(9H, s), 2.75(2H, m), 2.85˜3.60(8H, m), 3.75(1H,     m), 4.55(1H, ddd, J=6.4Hz×3), 6.17(1H, d, J=9.0Hz), 6.79(1H, t,     J=6.7Hz), 7.11(1H, d, J=2.0Hz), 7.26(5H, m), 7.55(1H, dd,  J=4.3Hz),     7.65(1H, t, J=7.8Hz), 8.05(1H, dd, J=1.4, 8.2Hz), 8.26(1H, dd, J=1.8,     8.3(Hz), 8.41(1H, dd, J=1.4, 7.2Hz), 8.58(1H, d, J=2.0Hz), 9.04(1H, dd,     J=1.8, 4.3Hz) 61 0.62˜1.75(13H, m), 1.34(9H, s), 2.70˜3.54(10     H, m), 3.62(1H, m), 3.89(1H, m), 4.61(1H, ddd, J=6.4Hz×3),     6.40(1H, t, J=6.8Hz), 6.48(1H, d, J=9.2Hz), 7.07(1H, dd, J=3.6, 5Hz),     7.25(6H, m), 7.40(1H, d,  J=6.8Hz), 8.70(1H, d, J=2Hz) 62 1.34(9H, m),     0.63˜1.78(13H, m), 2.74(1H, dt, J=6.5, 13.5Hz), 2.85˜3.52(8H,      m), 3.58(1H, dt, J=3.5, 6.6Hz), 4.59(1H, ddd, J=6.5Hz×3),     6.21(1H, t, J=6.4Hz), 6.42(1H, d, J=9.2Hz), 7.19(1H,  J=1.7Hz), 7.25(5H,     m), 7.41(1H, d, J=6.8Hz), 7.52(3H, m), 7.87(2H, m), 8.66(1H, d, J=2.0Hz)     63 0.60˜1.75(13H, m), 1.34(9H, s), 2.63(3H, s), 2.70(1H, dt,     J=6.6, 13.6Hz), 2.80˜3.46(9H, m), 3.53(1H, m), 3.87(1H, m),     4.47(1H, ddd, J=5.8Hz×3), 5.89(1H, t, J=7Hz), 6.41(1H, d, J=9Hz),     6.92(1H, s),  7.28(5H, m), 7.52(3H, m), 7.63(1H, d, J=5.8Hz), 7.86(2H,     dd, J=1.6, 7.7Hz) 64 0.76(3H, m), 1.13(1.43(1H, bd, J=9Hz), 1.60(4H, bd,     J=6Hz), 2.02(1H, bs), 2.52(6H, m), 2.72(1H, dd, J=10, 16Hz), 2.88(5H,     bt, J=7Hz), 3.03(2H, m), 3.26(2H, m), 3.45(8H, m), 3.75(4H, t, J=4.7Hz),     3.92  (1H, m), 3.98(1H, m), 4.68(1H, m), 5.17(1H, d, J=5.5Hz), 5.70(1H,     bt, J=5Hz), 6.50(1H, d, J=9.6Hz), 7.16(1H, d, J=2.0Hz), 7.34(5H, m),     8.87(1H, d, J=2.0Hz), 9.39(1H, d, J=6.9Hz) 65 0.74(3H, m), 0.9˜1.35     (5H, m), 1.45(1H, d, J=8Hz), 1.60(4H, m), 1.98(1H, bs), 2.24(2H, m),     2.39(2H, m), 2.55(4H, m), 2.80˜3.15(8H, m), 3.25(2H, t, J=7Hz),     3.30˜3.68(8H, m), 3.75(4H, m), 3.90(1H, dd,  J=4.4, 14.5Hz),     3.91(1H, m), 4.50(1H, m), 4.67(1H, m), 5.67(1H, bt), 6.73(1H, d,     J=9.2Hz), 7.15(1H, d, J=1.4Hz), 7.46(2H, m), 7.60(2H, m), 7.76(1H, d,     J=3.6Hz), 7.84(1H, dd, J=2.6, 6.8Hz), 7.92(1H, m),  8.16(1H, d, J=8.4Hz),      8.34(1H, d, J=7.2Hz), 8.60(1H, d, J=2Hz) 66 0.55˜1.74(13H, m),     2.02(2H, m), 2.18(1H, bs), 2.50(5H, m), 2.66˜2.94(3H, m), 2.94.abou     t.3.30(5H, m), 3.45(8H, m), 3.73(5H, m), 3.90(1H, m), 4.00(1H, m),     4.67(1H, m), 5.20(1H, bd), 5.78(1H, bt), 6.53(1H,  d, J=9.4Hz), 7.16(1H,     d, J=1.9Hz), 7.35(5H, m), 8.87(1H, d, J=2.0Hz), 9.41(1H, d, J=6.6Hz) 67     0.62˜1.75(13H, m), 2.04(2H, m), 2.20(2H, m), 2.39(2H, m), 2.51(6H,     m), 2.90(3H, m), 3.10(4H, m), 3.43(6H, ), 3.57(2H, m), 3.73(4H, m),     3.90(2H, m), 4.50(1H, m), 4.69(1H, m), 5.76(1H, bt), 6.77(1H,  d,     J=9Hz), 7.16(1H, d, J=1.4Hz), 7.44(2H, m), 7.60(2H, m), 7.76(1H, d,     J=3.2Hz), 7.85(1H, m), 7.90(1h, m), 8.16(1H, d, J=8Hz), 8.37(1H,d,     J=6.8Hz), 8.60(1H, d, J=2Hz) 68 0.73(3H, m), 1.15(5H, m), 1.43(1H, bd,     J=8Hz), 1.61(4H, bd, J=6Hz), 2.31(6H, s), 2.50(2H, m), 2.74(1H, dd,     J=10, 14Hz), 2.83(5H, m), 3.04(2H, m), 3.26(2H, m), 3.45(7H, m),     3.90(1H, m), 4.02(1H, dd,  J=2.8, 10.4Hz), 4.69(1H, m), 5.23(1H, bs),     6.51(1H, d, J=9Hz), 7.17(1H, d, J=1.6Hz), 7.35(5H, m), 7.35(5H, m),     8.87(1H, d, J=2Hz), 9.32(1H, d, J=7Hz) 69 0.70˜1.80(13H, m),     1.35(9H, s), 2.96(3H, s), 2.75(1H, bs), 2.87(˜2.50(9H, m),     3.65(1H, m), 3.45(1H, m), 4.63(1H, ddd, J=5.8Hz), 5.78(1H, t, J=6.6Hz),     6.50(1H, d, J=9.2Hz), 7.28(6H, m), 7.60(1H,  d, 6.2Hz), 8.77(1H, d,     J=2Hz) 70 0.70˜1.88(17H, m), 0.95(3H, t, J=7.2Hz), 2.87˜3.52(     12H, m), 3.63(1H, m), 3.94(1H, m), 4.63(1H, ddd, J=6.2Hz×3),     5.68(1H, t, J=6.4Hz), 6.45(1H, d, J=9Hz), 7.25(6H, m), 7.54(1H, d,     J=6.4Hz), 8.76  (1H, d, J=2Hz) 71 0.64˜1.88(17H, m), 0.94(3H, t,     J=7.2Hz), 2.28(1H, dd, J=6.4, 16.6Hz), 2.60˜3.80(19H, m), 4.04(1H,     m), 4.70(1H, ddd, J=4.7Hz×3), 5.57(1H, t, J=6.8Hz)

Renin inhibition potency of the compounds (I) of the invention wasdetermined in vitro and in vivo according to the procedure described inthe following Experiments.

EXPERIMENT 1 Potency in vitro

Commercially available lyophilized human plasma (Ortho, Bi-Level PlasmaRenin Control) was renatured by dissolving in water. Angiotensinogen wasallowed to react with intrinsic renin contained in the renatured plasmato generate angiotensin I (AI), which was quantitatively measured withradioimmunoassay (RIA). Thus, potency of the plasma renin was determinedon the basis of the AI production. For this purpose, Renin RIA kit(RENIN, RIABEAD^(R)) manufactured by Dinabott was used. All of thereagents necessary for the measurement of the AI production wereavailable from the attachment of the kit, and the measurement wasconducted according to the manufacturer's direction.

To the plasma (0.2 ml) were added all of the reagents, and the mixturewas combined with either of sample solutions (0.002 ml) of variousconcentrations which had been prepared by dissolving a test compound indifferent amount of ethanol. Ethanol (0.002 ml) containing no testcompound was used as a control solution. The amount of AI produced wasmeasured after 60 minutes incubation. Renin inhibition potency of testcompound was determined by comparing the amount of AI produced by asample solution with that produced by a control solution. Theconcentrations of the test compounds which inhibit renin activity by 50%(IC₅₀) are summarized in Table 11.

                                      TABLE 11                                    __________________________________________________________________________    Renin Inhibition in vitro                                                     Test Compound    Test Compound  Test Compound                                 (Example No.)                                                                           IC.sub.50                                                                            (Example No.)                                                                         IC.sub.50                                                                            (Example No.)                                                                         IC.sub.50                             __________________________________________________________________________     1        6.09   22      39.2   42      13                                     2        5.87   23      2.07   43      0.51                                   3        4.44   24      1.56   44      1.53                                   4        3.21   25      3.17   45      0.31                                   5        29.0   26      1.32   46      3.16                                   6        4.22   27      1.78   47      5.90                                   8        6.17   28      0.52   48      1.98                                   9        12.0   29      3.31   49      2.34                                  10        10.9   30      1.07   50      14.8                                  11        9.1    31      11.6   51      4.51                                  12        4.56   32      6.72   52      1.69                                  13        53.9   33      4.65   53      0.36                                  14        9.3    34      9.53   55      0.60                                  15        12.6   35      0.63   56      0.70                                  16        71.3   36      4.98   57      0.80                                  17        259    37      14.5   58      0.19                                  18        22.8   38      39.2   59      0.41                                  19        3.75   39      7.52   62      1.24                                  20        7.36   40      18.1   64      0.70                                  21        2.73   41      4.98   69      0.53                                                                  (1) (KRI-1314)                                                                        21.3                                                                  (2) (ES-6864)                                                                         3.75                                  __________________________________________________________________________    IC.sub.50 : nm                                                                (1) KRI-1314                                                                   ##STR319##                                                                   (2) ES-6864                                                                    ##STR320##                                                                   __________________________________________________________________________

EXPERIMENT 2 Potency in vivo

Crab-eating monkeys (Cynomolgus monkeys) (2.8-5.0 kg) were fed on lowsodium diet (Na 7.15 mg/100 g feed) for six days, during which themonkeys intramuscularly received furosemide (2 mg/kg body weight) everyother day from the second day of the experiment, in order to make themonkeys hyperrenin condition.

After seven days from the low sodium feeding, the monkeys wererestrained on a monkey chair. Compounds to be tested are dissolved in0.1M citric acid/physiological saline or suspended in water withaddition of β-cyclodextrin, and orally administered to the monkeys usinga stomach probe (15 mg/kg body weight). Two milliliters of blood wascollected from femoral vein before administration of the compounds and0.5, 1.5, 2.5 and 4 hours after the administration. For the bloodcollection, an injection syringe containing 30 μl of 6% aqueous EDTA.2Nasolution was used. The collected blood was transferred into a test tubeand centrifuged (3000 rpm, 10 minutes) at 4° C., and the resultantsupernatant was used to determine the renin content. Plasma reninactivity (AI(ng)/ml/h value) was measured using Radioimmunoassay kitcommercially available from Dinabott Co. in the same manner as in theforegoing in vitro test. Renin inhibition potencies of the compoundstested, which were expressed as a percentage of renin activity relativeto the activity before the administration, are listed in Table 12.

                  TABLE 12                                                        ______________________________________                                        Compound                                                                      Example No.                                                                              Max    Mean      4 h 6 h   8 h 24 h                                ______________________________________                                         1         33     22        22                                                 2         49     46        49                                                 8         60     52        60                                                21         55     37        55                                                24         99     90        77  56    42  28                                  26         83     71        69  99                                            27         81     65        81  73    64  28                                  28         97     74        97  89    83  53                                  33         95     85        68  82                                            35         39     30        39  23    24  14                                  39         46     28        12                                                40         44     30        44                                                41         95     89        87  76    54  18                                  43         98     86        95  83    70  11                                  44         99     97        91  81    71  21                                  47         59     47        55   6    18  34                                  48         98     88        88  63    33   0                                  49         92     84        78  72    51  12                                  50         93     59        58  42    29   0                                  51         80     48        35   0     0   0                                  53         96     85        94        73                                      56         93     72        82        85                                      57         100    97        89        80                                      58         83     71        82        67                                      ______________________________________                                         1) Administration rate of compound No. 1 is 30 mg/kg.                         2) Furosemide was not administered in case of Nos. 2 and 8.              

The compounds of the invention which are not listed in Table 12 showedsimilar inhibition potencies.

Vasodepressor activity of the compounds of the invention was alsomeasured with direct technique using an conscious monkey, where a monkeywas administered a compound of the invention orally or intravenously (asolution in Tween 20). The test results are shown in Table 13.

                  TABLE 13                                                        ______________________________________                                                                          Maximum                                     Compound   Administration                                                                            Dose       reduced BP                                  Example No.                                                                              route       (mg/kg)    (-ΔmmHg                               ______________________________________                                        43         p.o.        100        35                                                                 30         10                                                                 10          5                                          43         i.v.        3          --                                                                 1          20                                                                 0.3         5                                          44         i.v.        3          20                                                                 1           8                                                                 0.3         5                                          ______________________________________                                    

The above test results show that the compounds of the present inventionhave renin inhibition potency both in vitro and in vivo.

The compounds of the invention are thus useful for the treatment ofhypertension due to the renin inhibition when orally administered.However, other administration routes may be also effective.

As discussed previously, the compounds of the invention can beformulated into a pharmaceutical composition together with suitablecarriers or excipients. When the compounds of the invention are used asa hypotensive agent, suitable dosage is 0.01-50 mg/kg/day in one tothree divided does, preferably 0.05-10 mg/kg/day, when orallyadministered, and 1-5000 μg/kg/day, preferably 5-500 μg/kg/day, whenparenterally administered.

What is claimed is:
 1. A dipeptide derivative of formula (I): ##STR321##wherein: R¹ is dimethylamino;R² is carbamoyl, aryl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl,1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,3-pyridazinyl, 2-pyrazinyl, 3-triazolyl, 2-thiazolyl, 4-thiazolyl,5-tetrazolyl, 3-isothiazolyl, 2-pyrrolidinyl, 2-imidazolidinyl,4-pyrazolidinyl, 4-piperidyl, 2-piperadinyl, morpholino, C₁ -C₁₂alkyl-S--, C₁ -C₁₂ alkyl-2--CH₂ -- or C₃ -C₁₀ cycloalkyl-S-; R³ is aryl,2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,2-imidazolyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,3-pyridazinyl, 2-pyrazinyl, 3-triazolyl, 2-thiazolyl, 4-thiazolyl,5-tetrazolyl, 3-isothiazolyl, 2-pyrrolidinyl, 2-imidazolidinyl,4-pyrazolidinyl, 4-piperidyl, 2-piperadinyl, or morpholino; R⁴ is R^(4')--SO₂ or R^(4') --CO; R^(4') is aryl, C₁ -C₁₂ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl; C₃ -C₁₀ cycloaklyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 3-pyridazinyl, 2-pyrazinyl, 3-triazolyl,2-thiazolyl, 4-thiazolyl, 5-tetrazolyl, 3-isothiazolyl, 2-pyrrolidinyl,2-imidazolidinyl, 4-pyrazolidinyl, 4-piperidyl, 2-piperadinyl,4-indolyl, 7-indolyl, 5-quinolyl, 8-quinolyl, 8-isoquinolyl, ormorpholino; X is CH₂, NH, O, or S; and Y is CO or NHSO₂, wherein R¹, R²,R³ and R^(4') each may be substituted with one to three substituentsselected independently from the group consisting of hydroxy; halogen;trifluoromethyl; --CN; 2-thienyl; 3-thienyl; 2-furyl; 3-furyl;2-pyrrolyl; 3-pyrrolyl; 2-imidazolyl; 1-pyrazolyl; 2-pyridyl; 3-pyridyl;4-pyridyl; 2-pyrimidyl; 3-pyridazinyl; 2-pyrazinyl; 3-triazolyl;2-thiazolyl; 4-thiazolyl; 5-tetrazolyl; 3-isothiazolyl; 2-pyrrolidinyl;2-imidazolidinyl; 4-pyrazolidinyl; 4-piperidyl; 2-piperadinyl;4-indolyl; 7-indolyl; 5-quinolyl; 8-quinolyl; 8-isoquinolyl; morpholino;C₁ -C₆ alkyl; C₃ -C₁₀ cycloalkyl; --O-C₁ -C₆ alkyl; --S-C₁ -C₆ alkyl;--SO-C₁ -C₆ alkyl; --SO₂ -C₁ -C₆ alkyl; C₁ -C₆ alkylenedioxy; --CO-O-C₁-C₆ alkyl; --NHCO-C₁ -C₆ alkyl; --NHSO₂ -C₁ -C₆ alkyl; --NR⁵ R⁶ ;--O-CO-NR⁵ R⁶ ; --CO-NR⁵ R⁶ ; --O-C₁ -C₆ alkyl NR⁵ R⁶ ; R⁵ and R⁶ areindependently hydrogen, formyl or C₁ -C₆ alkyl, or R⁵ and R⁶, when takentogether with the nitrogen to which they are attached, form a cyclicamino group, with the proviso that the dipeptide derivative has at leastone morpholino radical, or an acid addition salt thereof.
 2. Thecompound as claimed in claim 1 wherein R² is optionally substituted2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,2-imidazolyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,3-pyridazinyl, 2-pyrazinyl, 3-triazolyl, 2-thiazolyl, 4-thiazolyl,5-tetrazolyl, 3-isothiazolyl, 2-pyrrolidinyl, 2-imidazolidinyl,4-pyrazolidinyl, 4-piperidyl, 2l-piperadinyl, or morpholino; R³ isoptionally substituted aryl; R⁴ is morpholinosulfonyl; and X is NH.